chr2-47783116-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000445503.5(MSH6):​c.-118G>A variant causes a 5 prime UTR, NMD transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,413,074 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0026 ( 15 hom. )

Consequence

MSH6
ENST00000445503.5 5_prime_UTR, NMD_transcript

Scores

2

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.275
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 Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.78).
BP6
Variant 2-47783116-G-A is Benign according to our data. Variant chr2-47783116-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 336435.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00212 (323/152070) while in subpopulation AMR AF= 0.00596 (91/15278). AF 95% confidence interval is 0.00497. There are 0 homozygotes in gnomad4. There are 157 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 15 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MSH6NM_000179.3 linkuse as main transcript upstream_gene_variant ENST00000234420.11 NP_000170.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MSH6ENST00000234420.11 linkuse as main transcript upstream_gene_variant 1 NM_000179.3 ENSP00000234420 P4P52701-1

Frequencies

GnomAD3 genomes
AF:
0.00213
AC:
323
AN:
151960
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000459
Gnomad AMI
AF:
0.00883
Gnomad AMR
AF:
0.00596
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.000189
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00278
Gnomad OTH
AF:
0.00623
GnomAD4 exome
AF:
0.00263
AC:
3317
AN:
1261004
Hom.:
15
Cov.:
17
AF XY:
0.00254
AC XY:
1594
AN XY:
628618
show subpopulations
Gnomad4 AFR exome
AF:
0.000532
Gnomad4 AMR exome
AF:
0.00302
Gnomad4 ASJ exome
AF:
0.0000881
Gnomad4 EAS exome
AF:
0.0000306
Gnomad4 SAS exome
AF:
0.000319
Gnomad4 FIN exome
AF:
0.0000484
Gnomad4 NFE exome
AF:
0.00312
Gnomad4 OTH exome
AF:
0.00259
GnomAD4 genome
AF:
0.00212
AC:
323
AN:
152070
Hom.:
0
Cov.:
33
AF XY:
0.00211
AC XY:
157
AN XY:
74344
show subpopulations
Gnomad4 AFR
AF:
0.000458
Gnomad4 AMR
AF:
0.00596
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.000189
Gnomad4 NFE
AF:
0.00278
Gnomad4 OTH
AF:
0.00616
Alfa
AF:
0.000159
Hom.:
0
Bravo
AF:
0.00257

ClinVar

Significance: Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Lynch syndrome 5 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
not provided Benign:1
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.78
CADD
Benign
6.7
DANN
Benign
0.86

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: rs556432240; hg19: chr2-48010255; API