rs1800932

Variant names:

• chr2-47790942-A-G
• rs1800932
• NM_000179.3:c.276A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-47790942-A-G
• chr2-47790942-A-T
• chr2-47790942-A-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000179.3(MSH6):​c.276A>G​(p.Pro92Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,613,796 control chromosomes in the GnomAD database, including 24,694 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. P92P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (1786 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22908 hom.)
• Consequence: MSH6 NM_000179.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:23
• Conservation: PhyloP100: 0.115
• Publications: 63 publications found

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]

FBXO11 (HGNC:13590): (F-box protein 11) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbxs class. It can function as an arginine methyltransferase that symmetrically dimethylates arginine residues, and it acts as an adaptor protein to mediate the neddylation of p53, which leads to the suppression of p53 function. This gene is known to be down-regulated in melanocytes from patients with vitiligo, a skin disorder that results in depigmentation. Polymorphisms in this gene are associated with chronic otitis media with effusion and recurrent otitis media (COME/ROM), a hearing loss disorder, and the knockout of the homologous mouse gene results in the deaf mouse mutant Jeff (Jf), a single gene model of otitis media. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jun 2010]

FBXO11 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with dysmorphic facies and behavioral abnormalities

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 2-47790942-A-G is Benign according to our data. Variant chr2-47790942-A-G is described in ClinVar as Benign. ClinVar VariationId is 36587.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=0.115 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000179.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	NM_000179.3	MANE Select	c.276A>G	p.Pro92Pro	synonymous	Exon 2 of 10	NP_000170.1	P52701-1
	MSH6	NM_001406795.1		c.372A>G	p.Pro124Pro	synonymous	Exon 3 of 11	NP_001393724.1
	MSH6	NM_001406813.1		c.276A>G	p.Pro92Pro	synonymous	Exon 2 of 10	NP_001393742.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	ENST00000234420.11	TSL:1 MANE Select	c.276A>G	p.Pro92Pro	synonymous	Exon 2 of 10	ENSP00000234420.5	P52701-1
	MSH6	ENST00000445503.5	TSL:1	n.276A>G		non_coding_transcript_exon	Exon 2 of 9	ENSP00000405294.1	F8WAX8
	MSH6	ENST00000936511.1		c.276A>G	p.Pro92Pro	synonymous	Exon 2 of 10	ENSP00000606570.1

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21823 AN: 152176 Hom.: 1787 Cov.: 32

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0591

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.164

GnomAD2 exomes AF: 0.135 AC: 33880 AN: 251472 AF XY: 0.137

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.0850

Gnomad ASJ exome AF: 0.172

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.124

Gnomad NFE exome AF: 0.190

Gnomad OTH exome AF: 0.152

GnomAD4 exome AF: 0.170 AC: 249074 AN: 1461502 Hom.: 22908 Cov.: 34 AF XY: 0.168 AC XY: 122076 AN XY: 727102

African (AFR) AF: 0.103 AC: 3439 AN: 33476

American (AMR) AF: 0.0907 AC: 4057 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 4313 AN: 26136

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39700

South Asian (SAS) AF: 0.0744 AC: 6413 AN: 86248

European-Finnish (FIN) AF: 0.122 AC: 6503 AN: 53418

Middle Eastern (MID) AF: 0.167 AC: 963 AN: 5768

European-Non Finnish (NFE) AF: 0.192 AC: 213895 AN: 1111644

Other (OTH) AF: 0.157 AC: 9477 AN: 60388

GnomAD4 genome AF: 0.143 AC: 21824 AN: 152294 Hom.: 1786 Cov.: 32 AF XY: 0.139 AC XY: 10325 AN XY: 74458

African (AFR) AF: 0.110 AC: 4565 AN: 41566

American (AMR) AF: 0.129 AC: 1974 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 533 AN: 3470

East Asian (EAS) AF: 0.000964 AC: 5 AN: 5186

South Asian (SAS) AF: 0.0590 AC: 285 AN: 4834

European-Finnish (FIN) AF: 0.122 AC: 1297 AN: 10612

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.186 AC: 12629 AN: 68016

Other (OTH) AF: 0.161 AC: 341 AN: 2114

Alfa AF: 0.160 Hom.: 2090

Bravo AF: 0.146

Asia WGS AF: 0.0450 AC: 160 AN: 3478

EpiCase AF: 0.208

EpiControl AF: 0.209

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	5	Lynch syndrome 5 (5)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not provided (3)
-	-	2	Lynch syndrome (2)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	9.5
DANN	Benign	0.75
PhyloP100		0.12
Mutation Taster		=75/25	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1800932; hg19: chr2-48018081; COSMIC: COSV52275820;