NM_194454.3:c.500G>A
Variant summary
Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2
The NM_194454.3(KRIT1):c.500G>A(p.Arg167His) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,613,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R167C) has been classified as Uncertain significance.
Frequency
Consequence
NM_194454.3 missense
Scores
Clinical Significance
Conservation
Publications
- cerebral cavernous malformation 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- famililal cerebral cavernous malformationsInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Benign. The variant received -7 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KRIT1 | ENST00000394505.7 | c.500G>A | p.Arg167His | missense_variant | Exon 8 of 19 | 1 | NM_194454.3 | ENSP00000378013.2 | ||
ENSG00000289027 | ENST00000692281.1 | c.500G>A | p.Arg167His | missense_variant | Exon 8 of 26 | ENSP00000510568.1 | ||||
ENSG00000285953 | ENST00000458493.6 | c.500G>A | p.Arg167His | missense_variant | Exon 7 of 20 | 4 | ENSP00000396352.2 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152020Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00000796 AC: 2AN: 251304 AF XY: 0.00000736 show subpopulations
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461460Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727054 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152020Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74244 show subpopulations
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
The c.500G>A (p.R167H) alteration is located in exon 9 (coding exon 5) of the KRIT1 gene. This alteration results from a G to A substitution at nucleotide position 500, causing the arginine (R) at amino acid position 167 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Cerebral cavernous malformation Uncertain:1
This sequence change replaces arginine with histidine at codon 167 of the KRIT1 protein (p.Arg167His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with KRIT1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at