rs2020906

Variant names:

• chr2-47806945-T-A
• rs2020906
• NM_000179.3:c.*85T>A

Your query was ambiguous. Multiple possible variants found:

• chr2-47806945-T-A
• chr2-47806945-T-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000179.3(MSH6):​c.*85T>A variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.00729 in 1,036,700 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene MSH6 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0062 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0075 (37 hom.)
• Consequence: MSH6 NM_000179.3 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 3.97
• Publications: 6 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

Specifications for MSH6 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 2-47806945-T-A is Benign according to our data. Variant chr2-47806945-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 89155.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00624 (950/152148) while in subpopulation NFE AF = 0.0092 (625/67946). AF 95% confidence interval is 0.0086. There are 4 homozygotes in GnomAd4. There are 524 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

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.*85T>A		3_prime_UTR	Exon 10 of 10	NP_000170.1	P52701-1
	FBXO11	NM_001190274.2	MANE Select	c.*1173A>T		3_prime_UTR	Exon 23 of 23	NP_001177203.1	Q86XK2-1
	MSH6	NM_001406795.1		c.*85T>A		3_prime_UTR	Exon 11 of 11	NP_001393724.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	ENST00000234420.11	TSL:1 MANE Select	c.*85T>A		3_prime_UTR	Exon 10 of 10	ENSP00000234420.5	P52701-1
	FBXO11	ENST00000403359.8	TSL:1 MANE Select	c.*1173A>T		3_prime_UTR	Exon 23 of 23	ENSP00000384823.4	Q86XK2-1
	FBXO11	ENST00000402508.5	TSL:1	c.*1173A>T		3_prime_UTR	Exon 23 of 23	ENSP00000385398.1	Q86XK2-6

Frequencies

GnomAD3 genomes AF: 0.00625 AC: 950 AN: 152030 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0214

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00920

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.00747 AC: 6612 AN: 884552 Hom.: 37 Cov.: 12 AF XY: 0.00720 AC XY: 3331 AN XY: 462708

African (AFR) AF: 0.00155 AC: 32 AN: 20664

American (AMR) AF: 0.000920 AC: 34 AN: 36964

Ashkenazi Jewish (ASJ) AF: 0.00179 AC: 39 AN: 21802

East Asian (EAS) AF: 0.000874 AC: 31 AN: 35468

South Asian (SAS) AF: 0.00287 AC: 199 AN: 69424

European-Finnish (FIN) AF: 0.0162 AC: 767 AN: 47346

Middle Eastern (MID) AF: 0.000218 AC: 1 AN: 4580

European-Non Finnish (NFE) AF: 0.00868 AC: 5269 AN: 607360

Other (OTH) AF: 0.00586 AC: 240 AN: 40944

GnomAD4 genome AF: 0.00624 AC: 950 AN: 152148 Hom.: 4 Cov.: 31 AF XY: 0.00704 AC XY: 524 AN XY: 74388

African (AFR) AF: 0.00144 AC: 60 AN: 41540

American (AMR) AF: 0.000720 AC: 11 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3466

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5180

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4822

European-Finnish (FIN) AF: 0.0214 AC: 227 AN: 10588

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00920 AC: 625 AN: 67946

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00923 Hom.: 0

Bravo AF: 0.00466

Asia WGS AF: 0.000867 AC: 3 AN: 3474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Endometrial carcinoma;C1833477:Lynch syndrome 5 (1)
-	-	1	Hereditary cancer (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	1	-	Lynch syndrome 5 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	10
DANN	Benign	0.81
PhyloP100		4.0
Mutation Taster		=97/3	polymorphism

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: rs2020906; hg19: chr2-48034084;