2-47799147-C-T

Variant names:

• chr2-47799147-C-T
• rs55708305
• NM_000179.3:c.1164C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000179.3(MSH6):​c.1164C>T​(p.His388His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,613,754 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.013 (36 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (44 hom.)
• Consequence: MSH6 NM_000179.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:21
• Conservation: PhyloP100: 0.424
• Publications: 8 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 2-47799147-C-T is Benign according to our data. Variant chr2-47799147-C-T is described in ClinVar as Benign. ClinVar VariationId is 42467.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=0.424 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0129 (1964/151874) while in subpopulation AFR AF = 0.0428 (1771/41380). AF 95% confidence interval is 0.0411. There are 36 homozygotes in GnomAd4. There are 959 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 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.1164C>T	p.His388His	synonymous	Exon 4 of 10	NP_000170.1	P52701-1
	MSH6	NM_001406795.1		c.1260C>T	p.His420His	synonymous	Exon 5 of 11	NP_001393724.1
	MSH6	NM_001406813.1		c.1170C>T	p.His390His	synonymous	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.1164C>T	p.His388His	synonymous	Exon 4 of 10	ENSP00000234420.5	P52701-1
	MSH6	ENST00000445503.5	TSL:1	n.*511C>T		non_coding_transcript_exon	Exon 3 of 9	ENSP00000405294.1	F8WAX8
	MSH6	ENST00000445503.5	TSL:1	n.*511C>T		3_prime_UTR	Exon 3 of 9	ENSP00000405294.1	F8WAX8

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1958 AN: 151756 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0428

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00952

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0159

GnomAD2 exomes AF: 0.00351 AC: 881 AN: 250986 AF XY: 0.00260

Gnomad AFR exome AF: 0.0436

Gnomad AMR exome AF: 0.00364

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00139 AC: 2034 AN: 1461880 Hom.: 44 Cov.: 34 AF XY: 0.00125 AC XY: 906 AN XY: 727236

African (AFR) AF: 0.0447 AC: 1496 AN: 33480

American (AMR) AF: 0.00418 AC: 187 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.000122 AC: 136 AN: 1112006

Other (OTH) AF: 0.00321 AC: 194 AN: 60396

GnomAD4 genome AF: 0.0129 AC: 1964 AN: 151874 Hom.: 36 Cov.: 32 AF XY: 0.0129 AC XY: 959 AN XY: 74276

African (AFR) AF: 0.0428 AC: 1771 AN: 41380

American (AMR) AF: 0.00951 AC: 145 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5158

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67940

Other (OTH) AF: 0.0157 AC: 33 AN: 2100

Alfa AF: 0.00818 Hom.: 27

Bravo AF: 0.0152

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	6.9
DANN	Benign	0.84
PhyloP100		0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	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: rs55708305; hg19: chr2-48026286; COSMIC: COSV104579421;