rs121908790

Positions:

• chr7-117504375-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BS2_Supporting

The NM_000492.4(CFTR):​c.164+12T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00024 in 1,260,782 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (5 hom.)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5 O:1
• Conservation: PhyloP100: -0.181

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 7-117504375-T-C is Benign according to our data. Variant chr7-117504375-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53302.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, not_provided=1, Uncertain_significance=4}.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.164+12T>C		intron_variant		ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.164+12T>C		intron_variant		1	NM_000492.4	ENSP00000003084	P2

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000343 AC: 85 AN: 247964 Hom.: 2 AF XY: 0.000485 AC XY: 65 AN XY: 134022

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00260

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000258 AC: 286 AN: 1108442 Hom.: 5 Cov.: 16 AF XY: 0.000355 AC XY: 202 AN XY: 568722

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000264

Gnomad4 SAS exome AF: 0.00316

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000304

Gnomad4 OTH exome AF: 0.000206

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74486

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000782 Hom.: 0

Bravo AF: 0.0000453

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Uncertain:3 Benign:3 Other:1

not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 28, 2023	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 21, 2017	The CFTR c.164+12T>C variant, which is often referred to as c.296+12T>C, has been reported in at least three studies and is found in a homozygous state in four individuals, three of whom were diagnosed with cystic fibrosis (CF) (Malone et al. 1998; Trujillano et al. 2015; Banjar et al. 2017). In a 6-year-old girl of Saudi descent, the c.164+12T>C variant was identified with a frameshift variant in a double homozygous state. The girl was reported to exhibit an earlier age of onset and lower BMI compared with other affected individuals (Banjar et al. 2017). The variant was shown to segregate with the disease in two families. The c.164+12T>C variant was absent from controls but is reported in a homozygous state in Exome Aggregation Consortium and Genome Aggregation Database. This variant is reported at a frequency of 0.019417 in the Gujarati Indian in Houston, Texas population of the 1000 Genomes Project, which is high but could be consistent with disease under-diagnosis in non-Caucasian populations. The evidence for this variant is limited. The c.164+12T>C variant is classified as unknown significance but suspicious for pathogenicity for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 03, 2020	- -
Uncertain significance, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM3, PP4, BS2, BP2, BP4 -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 24, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 10, 2017	- -

CFTR-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2024

The CFTR c.164+12T>C variant is predicted to interfere with splicing. This variant has been previously reported in homozygous state in individuals with cystic fibrosis (see for example: Trujillano et al. 2015. PubMed ID: 26436105 and Banjar et al. 2017. PubMed ID: 30805499). In one individual this variant was described as double homozygous, along with a second homozygous CFTR pathogenic variant (Banjar et al. 2017. PubMed ID: 30805499; ClinVarID:53841). This variant is reported in 0.26% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 25, 2024

Variant summary: CFTR c.164+12T>C alters a non-conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00034 in 247964 control chromosomes, predominantly at a frequency of 0.0026 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00034 vs 0.013), allowing no conclusion about variant significance. c.164+12T>C was reported in the homozygous state in two unrelated Cystic Fibrosis patients of Pakistani origin born to consanguineous parents (Malone_1998). However, due to the use of older mutational scanning technologies in this study, the possibility of missed co-occurrences with pathogenic variants in these patients cannot be ruled out. A more recent study reported the variant in one patient of Saudi Arabian descent with classic CF in homozygous state. However, the patient was also homozygous for another pathogenic CFTR variant (c.3889dupT, p.Ser1297PhefsX5) present in cis with the variant of interest (Banjar_2017). Another study (Lascano-Vaca_2020), reported the variant in heterozygous state in 2 pediatric CF patients from Ecuador with a detailed genotype provided for one of the patients who also had known pathogenic variants F508del and W1098X, providing further supporting evidence for a benign role. . To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12007216, 9482579, 22975760, 19645745, 12530290, 26436105, 32026723, 32143663). ClinVar contains an entry for this variant (Variation ID: 53302). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.18
DANN	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121908790; hg19: chr7-117144429;