Variant rs377502207 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000492.4(CFTR):c.2907A>C(p.Ala969Ala) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00000137 in 1,461,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CFTR
NM_000492.4 splice_region, synonymous

Scores

Splicing: ADA: 0.9906

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: 4.83

Variant links:

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]

CFTR links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.2907A>C	p.Ala969Ala	splice_region_variant, synonymous_variant	17/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.2907A>C	p.Ala969Ala	splice_region_variant, synonymous_variant	17/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251120

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135758

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461394

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726996

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:2Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 26, 2024	The c.2907A>C variant (also known as p.A969A), located in coding exon 17 of the CFTR gene, results from an A to C substitution at nucleotide position 2907. This nucleotide substitution does not change the alanine at codon 969. This variant has been identified in the homozygous state and/or in conjunction with other CFTR variant(s) in individuals with features consistent with cystic fibrosis or CFTR-related disorders (Tian X et al. Hum Genome Var, 2016 Jan;3:15063; Luo S et al. Gene, 2021 Jan;765:145045; Ambry internal data). In addition, RNA studies have demonstrated that this alteration results in exon skipping (Tian X et al. Hum Genome Var, 2016 Jan;3:15063). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 09, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 18, 2023	This sequence change affects codon 969 of the CFTR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CFTR protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs377502207, gnomAD 0.03%). This variant has been observed in individual(s) with congenital absence of vas deferens and/or cystic fibrosis who had a second CFTR variant (PMID: 27081564, 32777524). ClinVar contains an entry for this variant (Variation ID: 549917). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 27081564). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 02, 2024	Variant summary: CFTR c.2907A>C (p.Ala969Ala) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predicts the variant abolishes a 5 splicing donor site. Two predict the variant weakens a 5' donor site. Three predict the variant creates a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, demonstrating in a HEK293 cell minigene assay that c.2907A>C led to skipping of exon 17, predicted to result in a frameshift and a premature stop codon subject to nonsense mediated decay (example, Tian_2016). The variant allele was found at a frequency of 2.4e-05 in 251120 control chromosomes. c.2907A>C has been reported in the literature in the presumed compound heterozygous state or with 2 additional variants in individuals affected with Cystic Fibrosis and CBAVD (example, Tian_2016, Luo_2021). These data do not allow any conclusion about variant significance. The following publications have been ascertained in the context of this evaluation (PMID: 32777524, 27081564). ClinVar contains an entry for this variant (Variation ID: 549917). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

CFTR-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2023

The CFTR c.2907A>C variant is not predicted to result in an amino acid change (p.=). This variant is predicted to weaken the spice donor site at the exon 17/intron 17 boundary based on available splicing prediction programs (Alamut Visual Plus v1.6.1) and a functional study showed that this variant leads to skipping of exon 17 (Tian et al. 2016. PubMed ID: 27081564). This variant was reported in the compound heterozygous state in an individual with Cystic Fibrosis (C8, Tian et al. 2016. PubMed ID: 27081564) and was reported in three alleles in a study of individuals with congenital absence of the vas deferens (Table 1, No 45, Luo et al. 2021. PubMed ID: 32777524). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is reported in 0.033% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117243835-A-C) and has conflicting information regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain significance to likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/549917/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.44

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.44

Position offset: 1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over