2-47445624-G-T

Variant names:

• chr2-47445624-G-T
• rs1060504415
• NM_000251.3:c.1353G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001406658.1(MSH2):​c.-4G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSH2 NM_001406658.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.25

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1353G>T	p.Gln451His	missense_variant	Exon 8 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1353G>T	p.Gln451His	missense_variant	Exon 8 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D;.;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.63	D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	3.0	M;.;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.4	D;D;.;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.013	D;D;.;D
Sift4G	Uncertain	0.037	D;D;.;T
Polyphen		0.97	D;.;.;D
Vest4		0.59
MutPred		0.45		Loss of ubiquitination at K449 (P = 0.1166);.;Loss of ubiquitination at K449 (P = 0.1166);Loss of ubiquitination at K449 (P = 0.1166);
MVP		0.92
MPC		0.029
ClinPred		0.99	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.54

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: rs1060504415; hg19: chr2-47672763;