2-47800616-T-C

Variant names:

• chr2-47800616-T-C
• rs2020912
• NM_000179.3:c.2633T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001406795.1(MSH6):​c.2729T>C​(p.Val910Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00574 in 1,614,190 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V910G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0046 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (40 hom.)
• Consequence: MSH6 NM_001406795.1 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:34 O:1
• Conservation: PhyloP100: 0.373
• Publications: 64 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 47 uncertain in NM_001406795.1
• BP4: Computational evidence support a benign effect (MetaRNN=0.035881698).
• BP6: Variant 2-47800616-T-C is Benign according to our data. Variant chr2-47800616-T-C is described in ClinVar as Benign. ClinVar VariationId is 8931.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00462 (704/152330) while in subpopulation AMR AF = 0.00732 (112/15300). AF 95% confidence interval is 0.00662. There are 5 homozygotes in GnomAd4. There are 348 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406795.1. 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.2633T>C	p.Val878Ala	missense	Exon 4 of 10	NP_000170.1
	MSH6	NM_001406795.1		c.2729T>C	p.Val910Ala	missense	Exon 5 of 11	NP_001393724.1
	MSH6	NM_001406813.1		c.2639T>C	p.Val880Ala	missense	Exon 4 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.2633T>C	p.Val878Ala	missense	Exon 4 of 10	ENSP00000234420.5
	MSH6	ENST00000445503.5	TSL:1	n.*1980T>C		non_coding_transcript_exon	Exon 3 of 9	ENSP00000405294.1
	MSH6	ENST00000445503.5	TSL:1	n.*1980T>C		3_prime_UTR	Exon 3 of 9	ENSP00000405294.1

Frequencies

GnomAD3 genomes AF: 0.00465 AC: 708 AN: 152212 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00733

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00716

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.00511 AC: 1280 AN: 250386 AF XY: 0.00559

Gnomad AFR exome AF: 0.000879

Gnomad AMR exome AF: 0.00324

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00707

Gnomad OTH exome AF: 0.00656

GnomAD4 exome AF: 0.00586 AC: 8568 AN: 1461860 Hom.: 40 Cov.: 34 AF XY: 0.00607 AC XY: 4411 AN XY: 727234

African (AFR) AF: 0.000806 AC: 27 AN: 33480

American (AMR) AF: 0.00342 AC: 153 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00999 AC: 261 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.00650 AC: 561 AN: 86254

European-Finnish (FIN) AF: 0.000749 AC: 40 AN: 53412

Middle Eastern (MID) AF: 0.0170 AC: 98 AN: 5768

European-Non Finnish (NFE) AF: 0.00640 AC: 7114 AN: 1111994

Other (OTH) AF: 0.00517 AC: 312 AN: 60396

GnomAD4 genome AF: 0.00462 AC: 704 AN: 152330 Hom.: 5 Cov.: 32 AF XY: 0.00467 AC XY: 348 AN XY: 74494

African (AFR) AF: 0.000818 AC: 34 AN: 41560

American (AMR) AF: 0.00732 AC: 112 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4828

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00714 AC: 486 AN: 68036

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00597 Hom.: 14

Bravo AF: 0.00446

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00767 AC: 66

ExAC AF: 0.00524 AC: 636

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (12)
-	2	6	Lynch syndrome 5 (8)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	4	not provided (4)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Carcinoma of colon (1)
-	-	1	Colorectal / endometrial 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	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	8.0
DANN	Benign	0.73
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.37
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.15
Sift	Benign	0.34	T
Sift4G	Benign	0.48	T
Polyphen		0.036	B
Vest4		0.17
MVP		0.85
ClinPred		0.0017	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27
gMVP		0.45
Mutation Taster		=65/35	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: rs2020912; hg19: chr2-48027755; COSMIC: COSV52276766; COSMIC: COSV52276766;