rs11978434

Variant names:

• chr7-117591798-T-C
• rs11978434
• NM_000492.4:c.1767-136T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000492.4(CFTR):​c.1767-136T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.213 in 571,422 control chromosomes in the GnomAD database, including 14,909 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3563 hom., cov: 32)
  • Exomes 𝑓: 0.22 (11346 hom.)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.167

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 7-117591798-T-C is Benign according to our data. Variant chr7-117591798-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1177029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117591798-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1767-136T>C		intron_variant	Intron 13 of 26	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1767-136T>C		intron_variant	Intron 13 of 26	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30776 AN: 151948 Hom.: 3561 Cov.: 32

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.367

Gnomad MID AF: 0.179

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.190

GnomAD4 exome AF: 0.217 AC: 91110 AN: 419356 Hom.: 11346 AF XY: 0.213 AC XY: 46921 AN XY: 220250

Gnomad4 AFR exome AF: 0.158

Gnomad4 AMR exome AF: 0.146

Gnomad4 ASJ exome AF: 0.129

Gnomad4 EAS exome AF: 0.00605

Gnomad4 SAS exome AF: 0.145

Gnomad4 FIN exome AF: 0.349

Gnomad4 NFE exome AF: 0.241

Gnomad4 OTH exome AF: 0.202

GnomAD4 genome AF: 0.203 AC: 30795 AN: 152066 Hom.: 3563 Cov.: 32 AF XY: 0.205 AC XY: 15226 AN XY: 74334

Gnomad4 AFR AF: 0.154

Gnomad4 AMR AF: 0.169

Gnomad4 ASJ AF: 0.131

Gnomad4 EAS AF: 0.00289

Gnomad4 SAS AF: 0.131

Gnomad4 FIN AF: 0.367

Gnomad4 NFE AF: 0.239

Gnomad4 OTH AF: 0.193

Alfa AF: 0.221 Hom.: 4724

Bravo AF: 0.184

Asia WGS AF: 0.0870 AC: 302 AN: 3458

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

May 22, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.1767-136T>C is located at a position not widely known to affect splicing. 4/4 computational 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 0.23 in 31304 control chromosomes in the gnomAD database, including 993 homozygotes. The observed variant frequency is approximately 17.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in CFTR causing Cystic Fibrosis phenotype (0.013), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1767-136T>C in individuals affected with Cystic Fibrosis and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Cystic fibrosis Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CFTR-related disorder Benign:1

Nov 13, 2018

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:1

Jun 21, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.1
DANN	Benign	0.81

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: rs11978434; hg19: chr7-117231852;