rs2020910

Variant names:

• chr2-47803553-T-A
• rs2020910
• NM_000179.3:c.3306T>A

Your query was ambiguous. Multiple possible variants found:

• chr2-47803553-T-A
• chr2-47803553-T-C
• chr2-47803553-T-G

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.3306T>A​(p.Thr1102Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0098 in 1,614,072 control chromosomes in the GnomAD database, including 1,342 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. T1102T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (112 hom., cov: 32)
  • Exomes 𝑓: 0.0096 (1230 hom.)
• Consequence: MSH6 NM_000179.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:24
• Conservation: PhyloP100: -2.34
• Publications: 23 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=-0.64).
• BP6: Variant 2-47803553-T-A is Benign according to our data. Variant chr2-47803553-T-A is described in ClinVar as Benign. ClinVar VariationId is 36589.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=-2.34 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.187 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.3306T>A	p.Thr1102Thr	synonymous	Exon 5 of 10	NP_000170.1	P52701-1
	MSH6	NM_001406795.1		c.3402T>A	p.Thr1134Thr	synonymous	Exon 6 of 11	NP_001393724.1
	MSH6	NM_001406813.1		c.3312T>A	p.Thr1104Thr	synonymous	Exon 5 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.3306T>A	p.Thr1102Thr	synonymous	Exon 5 of 10	ENSP00000234420.5	P52701-1
	MSH6	ENST00000445503.5	TSL:1	n.*2653T>A		non_coding_transcript_exon	Exon 4 of 9	ENSP00000405294.1	F8WAX8
	MSH6	ENST00000445503.5	TSL:1	n.*2653T>A		3_prime_UTR	Exon 4 of 9	ENSP00000405294.1	F8WAX8

Frequencies

GnomAD3 genomes AF: 0.0115 AC: 1753 AN: 152080 Hom.: 112 Cov.: 32

Gnomad AFR AF: 0.00710

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00708

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.0133

Gnomad FIN AF: 0.0120

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.0125

GnomAD2 exomes AF: 0.0203 AC: 5099 AN: 251432 AF XY: 0.0186

Gnomad AFR exome AF: 0.00800

Gnomad AMR exome AF: 0.0137

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.203

Gnomad FIN exome AF: 0.0108

Gnomad NFE exome AF: 0.00171

Gnomad OTH exome AF: 0.0148

GnomAD4 exome AF: 0.00962 AC: 14066 AN: 1461874 Hom.: 1230 Cov.: 33 AF XY: 0.00952 AC XY: 6922 AN XY: 727234

African (AFR) AF: 0.00672 AC: 225 AN: 33478

American (AMR) AF: 0.0124 AC: 554 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26136

East Asian (EAS) AF: 0.243 AC: 9659 AN: 39696

South Asian (SAS) AF: 0.00851 AC: 734 AN: 86256

European-Finnish (FIN) AF: 0.0110 AC: 585 AN: 53420

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5768

European-Non Finnish (NFE) AF: 0.00132 AC: 1463 AN: 1112002

Other (OTH) AF: 0.0135 AC: 816 AN: 60396

GnomAD4 genome AF: 0.0115 AC: 1752 AN: 152198 Hom.: 112 Cov.: 32 AF XY: 0.0124 AC XY: 926 AN XY: 74424

African (AFR) AF: 0.00718 AC: 298 AN: 41524

American (AMR) AF: 0.00707 AC: 108 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.197 AC: 1017 AN: 5170

South Asian (SAS) AF: 0.0133 AC: 64 AN: 4816

European-Finnish (FIN) AF: 0.0120 AC: 127 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00163 AC: 111 AN: 68028

Other (OTH) AF: 0.0123 AC: 26 AN: 2106

Alfa AF: 0.00337 Hom.: 1

Bravo AF: 0.0121

Asia WGS AF: 0.0930 AC: 323 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.00160

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	4	Lynch syndrome 5 (4)
-	-	3	Lynch syndrome (3)
-	-	3	not provided (3)
-	-	1	Carcinoma of colon (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.27
DANN	Benign	0.71
PhyloP100		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs2020910; hg19: chr2-48030692; COSMIC: COSV52275019;