rs330792

Variant names:

• chr2-47781435-A-C
• rs330792
• ENST00000636749.1:n.57A>C

Your query was ambiguous. Multiple possible variants found:

• chr2-47781435-A-C
• chr2-47781435-A-G
• chr2-47781435-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000636749.1(U6):​n.57A>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 0.0888 in 152,110 control chromosomes in the GnomAD database, including 799 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.089 (794 hom., cov: 32)
  • Exomes 𝑓: 0.56 (5 hom.)
• Consequence: U6 ENST00000636749.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.551
• Publications: 10 publications found

Genes affected

U6 (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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.116 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
U6	ENST00000636749.1	n.57A>C		non_coding_transcript_exon_variant	Exon 1 of 1	6
MSH6	ENST00000652107.1	c.-37-9492A>C		intron_variant	Intron 3 of 11			ENSP00000498629.1
ENSG00000304164	ENST00000800214.1	n.250+1012T>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.0888 AC: 13495 AN: 151986 Hom.: 791 Cov.: 32

Gnomad AFR AF: 0.0224

Gnomad AMI AF: 0.0857

Gnomad AMR AF: 0.0938

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.0467

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.112

GnomAD4 exome AF: 0.556 AC: 10 AN: 18 Hom.: 5 Cov.: 0 AF XY: 0.600 AC XY: 6 AN XY: 10

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.625 AC: 10 AN: 16

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0887 AC: 13498 AN: 152092 Hom.: 794 Cov.: 32 AF XY: 0.0904 AC XY: 6720 AN XY: 74328

African (AFR) AF: 0.0224 AC: 928 AN: 41508

American (AMR) AF: 0.0936 AC: 1429 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 417 AN: 3472

East Asian (EAS) AF: 0.0466 AC: 241 AN: 5168

South Asian (SAS) AF: 0.112 AC: 538 AN: 4824

European-Finnish (FIN) AF: 0.146 AC: 1538 AN: 10542

Middle Eastern (MID) AF: 0.190 AC: 55 AN: 290

European-Non Finnish (NFE) AF: 0.118 AC: 8029 AN: 68002

Other (OTH) AF: 0.116 AC: 245 AN: 2104

Alfa AF: 0.111 Hom.: 1684

Bravo AF: 0.0794

Asia WGS AF: 0.0840 AC: 292 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.4
DANN	Benign	0.94
PhyloP100		0.55

Splicing

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

Other links and lift over

dbSNP: rs330792; hg19: chr2-48008574;