chr6-31740551-C-T

Variant names:

• chr6-31740551-C-T
• rs2075789
• NM_172166.4:c.85C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_172166.4(MSH5):​c.85C>T​(p.Pro29Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0982 in 1,526,338 control chromosomes in the GnomAD database, including 8,609 homozygotes. 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.093 (832 hom., cov: 31)
  • Exomes 𝑓: 0.099 (7777 hom.)
• Consequence: MSH5 NM_172166.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.0390
• Publications: 58 publications found

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]

CLIC1 (HGNC:2062): (chloride intracellular channel 1) Chloride channels are a diverse group of proteins that regulate fundamental cellular processes including stabilization of cell membrane potential, transepithelial transport, maintenance of intracellular pH, and regulation of cell volume. Chloride intracellular channel 1 is a member of the p64 family; the protein localizes principally to the cell nucleus and exhibits both nuclear and plasma membrane chloride ion channel activity. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004588902).
• BP6: Variant 6-31740551-C-T is Benign according to our data. Variant chr6-31740551-C-T is described in ClinVar as Benign. ClinVar VariationId is 403111.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172166.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH5	NM_172166.4	MANE Select	c.85C>T	p.Pro29Ser	missense	Exon 2 of 25	NP_751898.1	O43196-1
	MSH5	NM_172165.4		c.85C>T	p.Pro29Ser	missense	Exon 2 of 25	NP_751897.1	O43196-2
	MSH5	NM_002441.5		c.85C>T	p.Pro29Ser	missense	Exon 2 of 25	NP_002432.1	A0A024RCM1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH5	ENST00000375750.9	TSL:1 MANE Select	c.85C>T	p.Pro29Ser	missense	Exon 2 of 25	ENSP00000364903.3	O43196-1
	MSH5	ENST00000375703.7	TSL:1	c.85C>T	p.Pro29Ser	missense	Exon 2 of 25	ENSP00000364855.3	O43196-2
	MSH5	ENST00000375755.8	TSL:1	c.85C>T	p.Pro29Ser	missense	Exon 2 of 25	ENSP00000364908.3	O43196-1

Frequencies

GnomAD3 genomes AF: 0.0930 AC: 14131 AN: 152010 Hom.: 830 Cov.: 31

Gnomad AFR AF: 0.0350

Gnomad AMI AF: 0.0626

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.0404

Gnomad EAS AF: 0.149

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0960

Gnomad OTH AF: 0.0775

GnomAD2 exomes AF: 0.126 AC: 15944 AN: 126162 AF XY: 0.123

Gnomad AFR exome AF: 0.0332

Gnomad AMR exome AF: 0.217

Gnomad ASJ exome AF: 0.0424

Gnomad EAS exome AF: 0.138

Gnomad FIN exome AF: 0.175

Gnomad NFE exome AF: 0.0954

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.0988 AC: 135706 AN: 1374210 Hom.: 7777 Cov.: 31 AF XY: 0.0991 AC XY: 67201 AN XY: 678122

African (AFR) AF: 0.0306 AC: 893 AN: 29224

American (AMR) AF: 0.197 AC: 5879 AN: 29810

Ashkenazi Jewish (ASJ) AF: 0.0427 AC: 1021 AN: 23930

East Asian (EAS) AF: 0.213 AC: 7238 AN: 33982

South Asian (SAS) AF: 0.129 AC: 9961 AN: 77072

European-Finnish (FIN) AF: 0.177 AC: 8622 AN: 48762

Middle Eastern (MID) AF: 0.0502 AC: 243 AN: 4836

European-Non Finnish (NFE) AF: 0.0900 AC: 96329 AN: 1069930

Other (OTH) AF: 0.0974 AC: 5520 AN: 56664

GnomAD4 genome AF: 0.0930 AC: 14142 AN: 152128 Hom.: 832 Cov.: 31 AF XY: 0.0996 AC XY: 7406 AN XY: 74376

African (AFR) AF: 0.0350 AC: 1452 AN: 41536

American (AMR) AF: 0.165 AC: 2516 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0404 AC: 140 AN: 3464

East Asian (EAS) AF: 0.149 AC: 770 AN: 5156

South Asian (SAS) AF: 0.132 AC: 634 AN: 4814

European-Finnish (FIN) AF: 0.177 AC: 1869 AN: 10584

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0960 AC: 6524 AN: 67970

Other (OTH) AF: 0.0772 AC: 163 AN: 2112

Alfa AF: 0.0949 Hom.: 1053

Bravo AF: 0.0890

TwinsUK AF: 0.0912 AC: 338

ALSPAC AF: 0.0823 AC: 317

ESP6500AA AF: 0.0322 AC: 129

ESP6500EA AF: 0.0830 AC: 669

ExAC AF: 0.0822 AC: 8196

Asia WGS AF: 0.176 AC: 611 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	MSH5-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.7
DANN	Benign	0.92
DEOGEN2	Benign	0.074	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.034	N
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.039
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.057
Sift	Uncertain	0.022	D
Sift4G	Benign	0.11	T
Polyphen		0.0	B
Vest4		0.034
MPC		0.45
ClinPred		0.0040	T
GERP RS		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.026
gMVP		0.51
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2075789; hg19: chr6-31708328;