NM_000492.4:c.1265C>T

Variant names:

• chr7-117548696-C-T
• rs201880593
• NM_000492.4:c.1265C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000492.4(CFTR):​c.1265C>T​(p.Ser422Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 3.12

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-AS1 (HGNC:40144): (CFTR antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07513532).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1265C>T	p.Ser422Phe	missense_variant	Exon 10 of 27	ENST00000003084.11	NP_000483.3
CFTR-AS1	NR_149084.1	n.222-6157G>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1265C>T	p.Ser422Phe	missense_variant	Exon 10 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

Alfa AF: 0.0358 Hom.: 0

ExAC AF: 0.00323 AC: 392

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Uncertain:2

Jul 22, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 23, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S422F variant (also known as c.1265C>T), located in coding exon 10 of the CFTR gene, results from a C to T substitution at nucleotide position 1265. The serine at codon 422 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant was detected in an individual with cystic fibrosis or a CFTR-related disorder; however, complete genotype and phenotype information was not provided (Trujillano D et al. Mol Genet Genomic Med, 2015 Sep;3:396-403). This variant was previously reported in the SNPDatabase as rs201880593. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

CFTR-related disorder Uncertain:1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Feb 26, 2021

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:1

Jun 07, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CFTR p.Ser422Phe variant was not identified in the Cosmic or MutDB databases but was identified in dbSNP (ID: rs201880593), ClinVar (reported benign by the Center for Pediatric Genomics Medicine at the Children's Mercy Hospital and Clinics), Clinvitae and LOVD 3.0. The variant was identified in control databases in 966 of 248446 chromosomes at a frequency of 0.003888 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (Finnish) in 230 of 19926 chromosomes (freq: 0.01154), African in 201 of 18444 chromosomes (freq: 0.0109), Other in 54 of 6140 chromosomes (freq: 0.008795), European (non-Finnish) in 418 of 112262 chromosomes (freq: 0.003723), Latino in 40 of 33502 chromosomes (freq: 0.001194), East Asian in 16 of 18542 chromosomes (freq: 0.000863) and Ashkenazi Jewish in 7 of 10004 chromosomes (freq: 0.0007), but was not observed in the South Asian population. Trujillano et al. (2015) identified this variant in the heterozygous state in 1/177 cystic fibrosis patients but suggested the variant to be neutral (Trujillano_2015_PMID: 26436105). The p.Ser422 residue is conserved in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	18
DANN	Benign	0.89
DEOGEN2	Uncertain	0.53	D;T
Eigen	Benign	-0.081
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.075	T;T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.4	N;N
REVEL	Uncertain	0.42
Sift	Benign	0.090	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.68	P;.
Vest4		0.53
MVP		0.99
MPC		0.0054
ClinPred		0.031	T
GERP RS		3.0
Varity_R		0.074
gMVP		0.66

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: rs201880593; hg19: chr7-117188750; COSMIC: COSV50041360;