2-47791136-A-G
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_001406813.1(MSH6):c.463+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00592 in 1,610,210 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★★).
Frequency
Consequence
NM_001406813.1 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00454 AC: 689AN: 151812Hom.: 2 Cov.: 33
GnomAD3 exomes AF: 0.00521 AC: 1308AN: 250876Hom.: 8 AF XY: 0.00573 AC XY: 778AN XY: 135702
GnomAD4 exome AF: 0.00606 AC: 8841AN: 1458280Hom.: 50 Cov.: 31 AF XY: 0.00627 AC XY: 4553AN XY: 725736
GnomAD4 genome AF: 0.00453 AC: 689AN: 151930Hom.: 2 Cov.: 33 AF XY: 0.00439 AC XY: 326AN XY: 74316
ClinVar
Submissions by phenotype
not specified Benign:7
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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Lynch syndrome 5 Benign:6
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
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not provided Benign:4
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MSH6: BS1, BS2 -
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Hereditary cancer-predisposing syndrome Benign:4
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This alteration is classified as 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. -
Breast and/or ovarian cancer Benign:1
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Carcinoma of colon Benign:1
The c.457+13A>G variant has been previously reported in the literature in individuals with CRC (8/295 chromosomes) but the frequency in controls did not differ significantly from the cases tested (6/185 chromosomes) (Peterlongo_2003_14520694, Woods_2005_16203774). This variant was listed in dbSNP (rs1800933) 'with untested allele' and reported from the 1000 genomes 4 times (MAF of 0.002) The exome variant server reported this variant in a European cohort with the following frequency increasing the likelihood this variant does not have clinical significance: G=54/A=8546. Further, this variant does not occur within the splicing consensus sequence increasing the likelihood this variant does not have clinical significance. -
Lynch syndrome Benign:1
Multifactorial likelihood analysis posterior probability 0.001-0.049 -
Hereditary nonpolyposis colorectal neoplasms Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at