7-117509071-A-G
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1BP4_ModerateBS2_Supporting
The NM_000492.4(CFTR):āc.202A>Gā(p.Lys68Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000899 in 1,612,996 control chromosomes in the GnomAD database, including 2 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
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.202A>G | p.Lys68Glu | missense_variant | Exon 3 of 27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152224Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000159 AC: 40AN: 251006Hom.: 1 AF XY: 0.000251 AC XY: 34AN XY: 135664
GnomAD4 exome AF: 0.0000917 AC: 134AN: 1460654Hom.: 2 Cov.: 29 AF XY: 0.000128 AC XY: 93AN XY: 726724
GnomAD4 genome AF: 0.0000722 AC: 11AN: 152342Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7AN XY: 74496
ClinVar
Submissions by phenotype
Cystic fibrosis Uncertain:3Benign:1Other:1
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The p.K68E variant (also known as c.202A>G), located in coding exon 3 of the CFTR gene, results from an A to G substitution at nucleotide position 202. The lysine at codon 68 is replaced by glutamic acid, an amino acid with similar properties. This variant was described in an individual with mild cystic fibrosis phenotype, who had a splice site variant on the other chromosome (Kilinç MO et al. Am. J. Med. Genet., 2002 Dec;113:250-7). This alteration was also identified in heterozygous state in an individual with pancreatic insufficiency and elevated sweat chloride levels (Alibakhshi R et al. J. Cyst. Fibros., 2008 Mar;7:102-9). This variant was also reported in a pancreatitis cohort (Jalaly NY et al. Am J Gastroenterol, 2017 Aug;112:1320-1329). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
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not provided Uncertain:2
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CFTR-related disorder Uncertain:1
The CFTR c.202A>G variant is predicted to result in the amino acid substitution p.Lys68Glu. This variant, described at nucleotide position 334 in legacy nomenclature, has been reported in the compound heterozygous state in an individual with mild cystic fibrosis (CF) who had pancreatic sufficiency and a borderline sweat chloride test (60 mEq/L) and in an individual with CF with pancreatic insufficiency and elevated sweat chloride, in whom a second CFTR variant was not found (Kilinc et al. 2002. PubMed ID: 12439892; Alibakhshi et al. 2007. PubMed ID: 17662673). This variant has also been reported in the heterozygous state in individuals with CF or CFTR-related disorders, chronic obstructive pulmonary disease, chronic pancreatitis, and congenital absence of vas deferens (Table 1, Amato et al. 2011. PubMed ID: 22020151; Table 2, Trujillano et al. 2015. PubMed ID: 26436105; Table 1, Jalaly et al. 2017. PubMed ID: 28440306; Supplementary Table 1, Saferali et al. 2022. PubMed ID: 34996830). However, this variant has also been found in the heterozygous state in a control individual from a study of patients with chronic pancreatitis and a control individual from a study of patients with congenital bilateral absence of the vas deferens (Supporting Tables S4 and S5, Steiner et al. 2011. PubMed ID: 21520337). In vitro functional studies suggest that this variant impairs CFTR function, although the protein retains 40-60% residual activity compared to control (Table 1, Baldassarri et al. 2022. PubMed ID: 36552859). This variant is reported in 0.078% 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at