chr2-47783475-C-A

Position:

• chr2-47783475-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000179.3(MSH6):​c.242C>A​(p.Ala81Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000777 in 1,287,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A81T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: MSH6 NM_000179.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.28

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3017749).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.242C>A	p.Ala81Glu	missense_variant	1/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.242C>A	p.Ala81Glu	missense_variant	1/10	1	NM_000179.3	ENSP00000234420	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.77e-7 AC: 1 AN: 1287314 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 625858

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000225

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.0055	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	17
DANN	Benign	0.92
DEOGEN2	Benign	0.24	T;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.64	T;T
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.55	N;.
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.0	N;.
REVEL	Benign	0.21
Sift	Benign	0.046	D;.
Sift4G	Benign	0.88	T;T
Polyphen		0.0010	B;.
Vest4		0.29
MutPred		0.15		Loss of MoRF binding (P = 0.0648);.;
MVP		0.76
ClinPred		0.17	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.052
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: -5

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-48010614;