2-47783075-C-T

Position:

• chr2-47783075-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000652107.1(MSH6):​c.-37-7852C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0899 in 862,978 control chromosomes in the GnomAD database, including 4,218 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.073 (573 hom., cov: 33)
  • Exomes 𝑓: 0.094 (3645 hom.)
• Consequence: MSH6 ENST00000652107.1 intron
• Clinical Significance: Benign reviewed by expert panel B:4
• Conservation: PhyloP100: -0.469

Genes affected

MSH6 (HGNC:7329): (mutS homolog 6) This gene encodes a member of the DNA mismatch repair MutS family. In E. coli, the MutS protein helps in the recognition of mismatched nucleotides prior to their repair. A highly conserved region of approximately 150 aa, called the Walker-A adenine nucleotide binding motif, exists in MutS homologs. The encoded protein heterodimerizes with MSH2 to form a mismatch recognition complex that functions as a bidirectional molecular switch that exchanges ADP and ATP as DNA mismatches are bound and dissociated. Mutations in this gene may be associated with hereditary nonpolyposis colon cancer, colorectal cancer, and endometrial cancer. Transcripts variants encoding different isoforms have been described. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-47783075-C-T is Benign according to our data. Variant chr2-47783075-C-T is described in ClinVar as [Benign]. Clinvar id is 89158.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47783075-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000652107.1	c.-37-7852C>T		intron_variant				ENSP00000498629
MSH6	ENST00000445503.5			upstream_gene_variant		1		ENSP00000405294

Frequencies

GnomAD3 genomes AF: 0.0726 AC: 11022 AN: 151740 Hom.: 573 Cov.: 33

Gnomad AFR AF: 0.0202

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.0490

Gnomad ASJ AF: 0.0366

Gnomad EAS AF: 0.000583

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.0729

GnomAD4 exome AF: 0.0935 AC: 66524 AN: 711130 Hom.: 3645 Cov.: 9 AF XY: 0.0905 AC XY: 32500 AN XY: 359156

Gnomad4 AFR exome AF: 0.0167

Gnomad4 AMR exome AF: 0.0476

Gnomad4 ASJ exome AF: 0.0406

Gnomad4 EAS exome AF: 0.000160

Gnomad4 SAS exome AF: 0.0191

Gnomad4 FIN exome AF: 0.147

Gnomad4 NFE exome AF: 0.107

Gnomad4 OTH exome AF: 0.0776

GnomAD4 genome AF: 0.0726 AC: 11024 AN: 151848 Hom.: 573 Cov.: 33 AF XY: 0.0721 AC XY: 5352 AN XY: 74202

Gnomad4 AFR AF: 0.0202

Gnomad4 AMR AF: 0.0489

Gnomad4 ASJ AF: 0.0366

Gnomad4 EAS AF: 0.000584

Gnomad4 SAS AF: 0.0139

Gnomad4 FIN AF: 0.157

Gnomad4 NFE AF: 0.109

Gnomad4 OTH AF: 0.0716

Alfa AF: 0.0874 Hom.: 169

Bravo AF: 0.0621

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Benign:2

Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	MAF >1% -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.7
DANN	Benign	0.91

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs41540312; hg19: chr2-48010214;