rs140396626
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
The NM_194454.3(KRIT1):āc.589A>Gā(p.Thr197Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000911 in 1,613,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_194454.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KRIT1 | NM_194454.3 | c.589A>G | p.Thr197Ala | missense_variant | 8/19 | ENST00000394505.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KRIT1 | ENST00000394505.7 | c.589A>G | p.Thr197Ala | missense_variant | 8/19 | 1 | NM_194454.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152098Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251444Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135892
GnomAD4 exome AF: 0.0000944 AC: 138AN: 1461654Hom.: 0 Cov.: 31 AF XY: 0.0000894 AC XY: 65AN XY: 727160
GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 152098Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74292
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 16, 2018 | - - |
Cerebral cavernous malformation Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 18, 2023 | Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KRIT1 protein function. ClinVar contains an entry for this variant (Variation ID: 590746). This variant has not been reported in the literature in individuals affected with KRIT1-related conditions. This variant is present in population databases (rs140396626, gnomAD 0.009%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 197 of the KRIT1 protein (p.Thr197Ala). 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. - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 04, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at