2-47806652-GTAACTAAC-GTAAC

Variant names:

• chr2-47806652-GTAAC-G
• rs267608132
• NM_000179.3:c.4001+12_4001+15delACTA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000179.3(MSH6):​c.4001+12_4001+15delACTA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,607,176 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (5 hom.)
• Consequence: MSH6 NM_000179.3 intron
• Clinical Significance: Likely benign reviewed by expert panel U:2 B:28
• Conservation: PhyloP100: 1.29
• Publications: 7 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 -16 ACMG points.

• BP6: Variant 2-47806652-GTAAC-G is Benign according to our data. Variant chr2-47806652-GTAAC-G is described in ClinVar as Likely_benign. ClinVar VariationId is 89500.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00101 (154/151998) while in subpopulation EAS AF = 0.00328 (17/5186). AF 95% confidence interval is 0.00209. There are 0 homozygotes in GnomAd4. There are 73 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 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.4001+12_4001+15delACTA		intron	N/A	NP_000170.1	P52701-1
	MSH6	NM_001406795.1		c.4097+12_4097+15delACTA		intron	N/A	NP_001393724.1
	MSH6	NM_001406813.1		c.4007+12_4007+15delACTA		intron	N/A	NP_001393742.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH6	ENST00000234420.11	TSL:1 MANE Select	c.4001+12_4001+15delACTA		intron	N/A	ENSP00000234420.5	P52701-1
	MSH6	ENST00000445503.5	TSL:1	n.*3348+12_*3348+15delACTA		intron	N/A	ENSP00000405294.1	F8WAX8
	MSH6	ENST00000936511.1		c.4028+12_4028+15delACTA		intron	N/A	ENSP00000606570.1

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 154 AN: 151882 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000653

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000787

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00327

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00122 AC: 299 AN: 244224 AF XY: 0.00108

Gnomad AFR exome AF: 0.00108

Gnomad AMR exome AF: 0.00172

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00326

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00121

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00131 AC: 1909 AN: 1455178 Hom.: 5 AF XY: 0.00133 AC XY: 965 AN XY: 724202

African (AFR) AF: 0.000419 AC: 14 AN: 33378

American (AMR) AF: 0.00166 AC: 74 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26100

East Asian (EAS) AF: 0.00310 AC: 123 AN: 39626

South Asian (SAS) AF: 0.000836 AC: 72 AN: 86094

European-Finnish (FIN) AF: 0.0000200 AC: 1 AN: 49916

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5760

European-Non Finnish (NFE) AF: 0.00139 AC: 1542 AN: 1109412

Other (OTH) AF: 0.00115 AC: 69 AN: 60242

GnomAD4 genome AF: 0.00101 AC: 154 AN: 151998 Hom.: 0 Cov.: 32 AF XY: 0.000982 AC XY: 73 AN XY: 74306

African (AFR) AF: 0.000652 AC: 27 AN: 41440

American (AMR) AF: 0.000786 AC: 12 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00328 AC: 17 AN: 5186

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10550

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

European-Non Finnish (NFE) AF: 0.00128 AC: 87 AN: 67952

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000582 Hom.: 0

Bravo AF: 0.000994

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	8	not provided (8)
-	-	6	not specified (6)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	3	Lynch syndrome 5 (3)
-	-	2	Lynch syndrome (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Endometrial carcinoma;C1833477:Lynch syndrome 5;C5436807:Mismatch repair cancer syndrome 3 (1)
-	1	-	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	1	-	Lynch syndrome 1 (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=20/80	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs267608132; hg19: chr2-48033791; COSMIC: COSV104579425;