2-47782677-T-G

Variant names:

• chr2-47782677-T-G
• rs3136228
• ENST00000800214.1:n.20A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000800214.1(ENSG00000304164):​n.20A>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.291 in 152,188 control chromosomes in the GnomAD database, including 7,066 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Genomes: 𝑓 0.29 (7066 hom., cov: 33)
• Consequence: ENSG00000304164 ENST00000800214.1 non_coding_transcript_exon
• Clinical Significance: Benign reviewed by expert panel B:1
• Conservation: PhyloP100: 0.0530
• Publications: 21 publications found

Genes affected

ENSG00000304164 (HGNC:):

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]

MSH6 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Lynch syndrome 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Muir-Torre syndrome

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-47782677-T-G is Benign according to our data. Variant chr2-47782677-T-G is described in ClinVar as [Benign]. Clinvar id is 89163.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.361 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000304164	ENST00000800214.1	n.20A>C		non_coding_transcript_exon_variant	Exon 1 of 2
MSH6	ENST00000652107.1	c.-37-8250T>G		intron_variant	Intron 3 of 11			ENSP00000498629.1

Frequencies

GnomAD3 genomes AF: 0.291 AC: 44313 AN: 152070 Hom.: 7057 Cov.: 33

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.254

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.00406

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.365

Gnomad OTH AF: 0.311

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.291 AC: 44339 AN: 152188 Hom.: 7066 Cov.: 33 AF XY: 0.284 AC XY: 21130 AN XY: 74400

African (AFR) AF: 0.243 AC: 10090 AN: 41528

American (AMR) AF: 0.230 AC: 3513 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.267 AC: 926 AN: 3472

East Asian (EAS) AF: 0.00407 AC: 21 AN: 5158

South Asian (SAS) AF: 0.132 AC: 636 AN: 4824

European-Finnish (FIN) AF: 0.323 AC: 3419 AN: 10596

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.365 AC: 24786 AN: 67990

Other (OTH) AF: 0.306 AC: 648 AN: 2116

Alfa AF: 0.336 Hom.: 32044

Bravo AF: 0.284

Asia WGS AF: 0.0910 AC: 319 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Benign:1

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: research

MAF >1% -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.3
DANN	Benign	0.44
PhyloP100		0.053
PromoterAI		0.019	Neutral

Splicing

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

Other links and lift over

dbSNP: rs3136228; hg19: chr2-48009816;