6-31741261-C-G

Position:

• chr6-31741261-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_172166.4(MSH5):​c.246C>G​(p.His82Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 151,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 31)
• Consequence: MSH5 NM_172166.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.04

Genes affected

MSH5 (HGNC:7328): (mutS homolog 5) This gene encodes a member of the mutS family of proteins that are involved in DNA mismatch repair and meiotic recombination. This protein is similar to a Saccharomyces cerevisiae protein that participates in segregation fidelity and crossing-over events during meiosis. This protein plays a role in promoting ionizing radiation-induced apoptosis. This protein forms hetero-oligomers with another member of this family, mutS homolog 4. Polymorphisms in this gene have been linked to various human diseases, including IgA deficiency, common variable immunodeficiency, and premature ovarian failure. Alternative splicing results multiple transcript variants. Read-through transcription also exists between this gene and the downstream chromosome 6 open reading frame 26 (C6orf26) gene. [provided by RefSeq, Feb 2011]

MSH5-SAPCD1 (HGNC:41994): (MSH5-SAPCD1 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring mutS homolog 5 (MSH5) and chromosome 6 open reading frame 26 (C6orf26) genes. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

MSH5 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053730816).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH5	NM_172166.4	c.246C>G	p.His82Gln	missense_variant	3/25	ENST00000375750.9	NP_751898.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH5	ENST00000375750.9	c.246C>G	p.His82Gln	missense_variant	3/25	1	NM_172166.4	ENSP00000364903.3
MSH5-SAPCD1	ENST00000493662.6	n.246C>G		non_coding_transcript_exon_variant	3/29	1		ENSP00000417871.2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151578 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151578 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73994

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 27, 2021

The c.246C>G (p.H82Q) alteration is located in exon 3 (coding exon 2) of the MSH5 gene. This alteration results from a C to G substitution at nucleotide position 246, causing the histidine (H) at amino acid position 82 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.0080
DANN	Benign	0.75
DEOGEN2	Benign	0.082	T;T;.;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.051	N
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.054	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;.;L;L
PROVEAN	Benign	-0.75	N;N;N;N;N
REVEL	Benign	0.026
Sift	Benign	0.34	T;T;T;T;T
Sift4G	Benign	0.24	T;T;T;T;T
Polyphen		0.0010	B;B;.;B;B
Vest4		0.081
MutPred		0.29		Gain of ubiquitination at K86 (P = 0.0985);Gain of ubiquitination at K86 (P = 0.0985);Gain of ubiquitination at K86 (P = 0.0985);Gain of ubiquitination at K86 (P = 0.0985);Gain of ubiquitination at K86 (P = 0.0985);
MVP		0.25
MPC		0.45
ClinPred		0.097	T
GERP RS		-9.5
Varity_R		0.040
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs779976920; hg19: chr6-31709038;