NM_000179.3:c.642C>T

Variant names:

• chr2-47798625-C-T
• rs1800937
• NM_000179.3:c.642C>T

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.642C>T​(p.Tyr214Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0912 in 1,610,204 control chromosomes in the GnomAD database, including 7,851 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.072 (550 hom., cov: 32)
  • Exomes 𝑓: 0.093 (7301 hom.)
• Consequence: MSH6 NM_000179.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:25
• Conservation: PhyloP100: -2.00
• Publications: 39 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=-0.82).
• BP6: Variant 2-47798625-C-T is Benign according to our data. Variant chr2-47798625-C-T is described in ClinVar as Benign. ClinVar VariationId is 36599.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=-2 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.106 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.642C>T	p.Tyr214Tyr	synonymous	Exon 4 of 10	NP_000170.1	P52701-1
	MSH6	NM_001281493.2		c.-265C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 9	NP_001268422.1	P52701-4
	MSH6	NM_001281494.2		c.-265C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 10	NP_001268423.1	P52701-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	ENST00000234420.11	TSL:1 MANE Select	c.642C>T	p.Tyr214Tyr	synonymous	Exon 4 of 10	ENSP00000234420.5	P52701-1
	MSH6	ENST00000445503.5	TSL:1	n.472C>T		non_coding_transcript_exon	Exon 3 of 9	ENSP00000405294.1	F8WAX8
	MSH6	ENST00000936511.1		c.642C>T	p.Tyr214Tyr	synonymous	Exon 4 of 10	ENSP00000606570.1

Frequencies

GnomAD3 genomes AF: 0.0719 AC: 10921 AN: 151930 Hom.: 550 Cov.: 32

Gnomad AFR AF: 0.0199

Gnomad AMI AF: 0.0451

Gnomad AMR AF: 0.0485

Gnomad ASJ AF: 0.0363

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.0727

GnomAD2 exomes AF: 0.0711 AC: 17523 AN: 246622 AF XY: 0.0710

Gnomad AFR exome AF: 0.0168

Gnomad AMR exome AF: 0.0336

Gnomad ASJ exome AF: 0.0376

Gnomad EAS exome AF: 0.0000547

Gnomad FIN exome AF: 0.149

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.0670

GnomAD4 exome AF: 0.0932 AC: 135926 AN: 1458156 Hom.: 7301 Cov.: 34 AF XY: 0.0909 AC XY: 65945 AN XY: 725442

African (AFR) AF: 0.0152 AC: 508 AN: 33478

American (AMR) AF: 0.0350 AC: 1563 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0390 AC: 1020 AN: 26130

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39698

South Asian (SAS) AF: 0.0179 AC: 1547 AN: 86238

European-Finnish (FIN) AF: 0.145 AC: 7276 AN: 50276

Middle Eastern (MID) AF: 0.0184 AC: 105 AN: 5702

European-Non Finnish (NFE) AF: 0.107 AC: 119206 AN: 1111562

Other (OTH) AF: 0.0778 AC: 4695 AN: 60352

GnomAD4 genome AF: 0.0718 AC: 10923 AN: 152048 Hom.: 550 Cov.: 32 AF XY: 0.0713 AC XY: 5296 AN XY: 74304

African (AFR) AF: 0.0198 AC: 823 AN: 41476

American (AMR) AF: 0.0485 AC: 740 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0363 AC: 126 AN: 3470

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5182

South Asian (SAS) AF: 0.0139 AC: 67 AN: 4820

European-Finnish (FIN) AF: 0.156 AC: 1641 AN: 10532

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.108 AC: 7327 AN: 67982

Other (OTH) AF: 0.0714 AC: 151 AN: 2114

Alfa AF: 0.0806 Hom.: 655

Bravo AF: 0.0614

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.0940

EpiControl AF: 0.0920

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	5	Lynch syndrome 5 (5)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	3	not provided (3)
-	-	2	Lynch syndrome (2)
-	-	1	Carcinoma of colon (1)
-	-	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
AlphaMissense	Benign	0.25
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.23
DANN	Benign	0.92
PhyloP100		-2.0
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Mutation Taster		=299/1	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: rs1800937; hg19: chr2-48025764; COSMIC: COSV52279626; COSMIC: COSV52279626;