rs397508369

Positions:

• chr7-117592513-C-A
• chr7-117592513-C-T

Variant summary

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

The NM_000492.4(CFTR):​c.2346C>A​(p.Asn782Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000058 in 1,379,088 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000058 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 0.903

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 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	c.2346C>A	p.Asn782Lys	missense_variant	14/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.2346C>A	p.Asn782Lys	missense_variant	14/27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000580 AC: 8 AN: 1379088 Hom.: 0 Cov.: 32 AF XY: 0.00000885 AC XY: 6 AN XY: 677676

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000142

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000651

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 05, 2023

Variant summary: CFTR c.2346C>A (p.Asn782Lys) results in a non-conservative amino acid change located in the CFTR regulator domain (IPR025837) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 184680 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2346C>A has been reported in the literature as a non-informative genotype (second allele not specified) in at-least one individual affected with Primary Sclerosing Cholangitis (PSC) (example, Giordon_2002, cited in Gallegos-Orozco_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. The following publications have been ascertained in the context of this evaluation (PMID: 15784035, 12127423). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Apr 27, 2021

- -

Cystic fibrosis Other:1

not provided, no classification provided

literature only

ClinVar Staff, National Center for Biotechnology Information (NCBI)

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	0.0063	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	4.7
DANN	Benign	0.30
DEOGEN2	Uncertain	0.48	T;.;T;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.71	T;T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.44	T;T;T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.90	L;.;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.15	N;.;N;.
REVEL	Uncertain	0.30
Sift	Benign	0.36	T;.;T;.
Sift4G	Benign	1.0	T;.;T;.
Polyphen		0.010	B;.;.;.
Vest4		0.72
MutPred		0.74		Gain of glycosylation at N782 (P = 0.0172);.;.;.;
MVP		0.98
MPC		0.0038
ClinPred		0.23	T
GERP RS		4.4
Varity_R		0.035
gMVP		0.19

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: rs397508369; hg19: chr7-117232567;