2-47795976-T-C

Variant names:

• chr2-47795976-T-C
• rs1800935
• NM_000179.3:c.540T>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.540T>C​(p.Asp180Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.264 in 1,613,852 control chromosomes in the GnomAD database, including 61,405 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4556 hom., cov: 32)
  • Exomes 𝑓: 0.27 (56849 hom.)
• Consequence: MSH6 NM_000179.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:24
• Conservation: PhyloP100: 0.457
• Publications: 54 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=-0.61).
• BP6: Variant 2-47795976-T-C is Benign according to our data. Variant chr2-47795976-T-C is described in ClinVar as Benign. ClinVar VariationId is 36597.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=0.457 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.293 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.540T>C	p.Asp180Asp	synonymous	Exon 3 of 10	NP_000170.1	P52701-1
	MSH6	NM_001406795.1		c.636T>C	p.Asp212Asp	synonymous	Exon 4 of 11	NP_001393724.1
	MSH6	NM_001406813.1		c.546T>C	p.Asp182Asp	synonymous	Exon 3 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.540T>C	p.Asp180Asp	synonymous	Exon 3 of 10	ENSP00000234420.5	P52701-1
	MSH6	ENST00000445503.5	TSL:1	n.458-2635T>C		intron	N/A	ENSP00000405294.1	F8WAX8
	MSH6	ENST00000936511.1		c.540T>C	p.Asp180Asp	synonymous	Exon 3 of 10	ENSP00000606570.1

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35162 AN: 151978 Hom.: 4554 Cov.: 32

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.0786

Gnomad FIN AF: 0.281

Gnomad MID AF: 0.201

Gnomad NFE AF: 0.296

Gnomad OTH AF: 0.254

GnomAD2 exomes AF: 0.213 AC: 53530 AN: 251342 AF XY: 0.215

Gnomad AFR exome AF: 0.168

Gnomad AMR exome AF: 0.124

Gnomad ASJ exome AF: 0.211

Gnomad EAS exome AF: 0.000816

Gnomad FIN exome AF: 0.276

Gnomad NFE exome AF: 0.300

Gnomad OTH exome AF: 0.226

GnomAD4 exome AF: 0.268 AC: 391651 AN: 1461754 Hom.: 56849 Cov.: 36 AF XY: 0.263 AC XY: 191232 AN XY: 727164

African (AFR) AF: 0.167 AC: 5592 AN: 33478

American (AMR) AF: 0.132 AC: 5885 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 5363 AN: 26136

East Asian (EAS) AF: 0.000680 AC: 27 AN: 39700

South Asian (SAS) AF: 0.0969 AC: 8362 AN: 86256

European-Finnish (FIN) AF: 0.272 AC: 14522 AN: 53416

Middle Eastern (MID) AF: 0.195 AC: 1124 AN: 5768

European-Non Finnish (NFE) AF: 0.302 AC: 336194 AN: 1111886

Other (OTH) AF: 0.241 AC: 14582 AN: 60390

GnomAD4 genome AF: 0.231 AC: 35178 AN: 152098 Hom.: 4556 Cov.: 32 AF XY: 0.226 AC XY: 16801 AN XY: 74354

African (AFR) AF: 0.178 AC: 7368 AN: 41494

American (AMR) AF: 0.188 AC: 2869 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 664 AN: 3470

East Asian (EAS) AF: 0.00173 AC: 9 AN: 5188

South Asian (SAS) AF: 0.0789 AC: 381 AN: 4828

European-Finnish (FIN) AF: 0.281 AC: 2969 AN: 10564

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.296 AC: 20149 AN: 67968

Other (OTH) AF: 0.250 AC: 526 AN: 2108

Alfa AF: 0.273 Hom.: 20508

Bravo AF: 0.225

Asia WGS AF: 0.0620 AC: 219 AN: 3478

EpiCase AF: 0.305

EpiControl AF: 0.304

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	Endometrial carcinoma;C1833477:Lynch syndrome 5;C5436807:Mismatch repair cancer syndrome 3 (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	7.7
DANN	Benign	0.76
PhyloP100		0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=94/6	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: rs1800935; hg19: chr2-48023115; COSMIC: COSV52274383; COSMIC: COSV52274383;