2-47408480-G-C

Position:

• chr2-47408480-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001406654.1(MSH2):​c.-129-1G>C variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MSH2 NM_001406654.1 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.647

Genes affected

MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

MSH2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.031543054 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.5, offset of 5, new splice context is: cttctggttcgtcactatAGagt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.291G>C	p.Gln97His	missense_variant	2/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.291G>C	p.Gln97His	missense_variant	2/16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460280 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726524

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: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Uncertain	0.72	D;D;.;.;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.87	D;T;D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.33	T;T;T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.6	L;.;.;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.6	D;D;N;.;N
REVEL	Uncertain	0.53
Sift	Benign	0.15	T;T;T;.;T
Sift4G	Benign	0.16	T;D;T;.;T
Polyphen		0.0010	B;.;.;.;B
Vest4		0.28
MutPred		0.66		Loss of solvent accessibility (P = 0.0217);.;.;Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);
MVP		0.96
MPC		0.0070
ClinPred		0.34	T
GERP RS		1.3
Varity_R		0.23
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

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: chr2-47635619;