2-47783183-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_000179.3(MSH6):​c.-51G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,606,646 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000074 ( 1 hom. )

Consequence

MSH6
NM_000179.3 5_prime_UTR

Scores

2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.18
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.84).
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000473 (72/152296) while in subpopulation AFR AF= 0.00168 (70/41578). AF 95% confidence interval is 0.00137. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MSH6NM_000179.3 linkuse as main transcriptc.-51G>T 5_prime_UTR_variant 1/10 ENST00000234420.11 NP_000170.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MSH6ENST00000234420.11 linkuse as main transcriptc.-51G>T 5_prime_UTR_variant 1/101 NM_000179.3 ENSP00000234420 P4P52701-1

Frequencies

GnomAD3 genomes
AF:
0.000467
AC:
71
AN:
152184
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00166
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000155
AC:
37
AN:
238262
Hom.:
1
AF XY:
0.000115
AC XY:
15
AN XY:
130688
show subpopulations
Gnomad AFR exome
AF:
0.00183
Gnomad AMR exome
AF:
0.000239
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000677
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000342
GnomAD4 exome
AF:
0.0000736
AC:
107
AN:
1454350
Hom.:
1
Cov.:
30
AF XY:
0.0000594
AC XY:
43
AN XY:
723628
show subpopulations
Gnomad4 AFR exome
AF:
0.00207
Gnomad4 AMR exome
AF:
0.000226
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000703
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.01e-7
Gnomad4 OTH exome
AF:
0.000333
GnomAD4 genome
AF:
0.000473
AC:
72
AN:
152296
Hom.:
0
Cov.:
33
AF XY:
0.000470
AC XY:
35
AN XY:
74474
show subpopulations
Gnomad4 AFR
AF:
0.00168
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000428
Hom.:
0
Bravo
AF:
0.000457
Asia WGS
AF:
0.000289
AC:
1
AN:
3476

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Lynch syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.84
CADD
Benign
1.6
DANN
Benign
0.56
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs375109921; hg19: chr2-48010322; API