chr2-47804894-C-T

Variant names:

• chr2-47804894-C-T
• rs192614006
• NM_000179.3:c.3439-16C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000179.3(MSH6):​c.3439-16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00386 in 1,593,988 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (21 hom.)
• Consequence: MSH6 NM_000179.3 intron
• Clinical Significance: Benign reviewed by expert panel U:1 B:22
• Conservation: PhyloP100: 0.472
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 2-47804894-C-T is Benign according to our data. Variant chr2-47804894-C-T is described in ClinVar as Benign. ClinVar VariationId is 89389.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00223 (339/152294) while in subpopulation NFE AF = 0.00385 (262/68024). AF 95% confidence interval is 0.00347. There are 0 homozygotes in GnomAd4. There are 142 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 21 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.3439-16C>T		intron	N/A	NP_000170.1	P52701-1
	MSH6	NM_001406795.1		c.3535-16C>T		intron	N/A	NP_001393724.1
	MSH6	NM_001406813.1		c.3445-16C>T		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.3439-16C>T		intron	N/A	ENSP00000234420.5	P52701-1
	MSH6	ENST00000445503.5	TSL:1	n.*2786-16C>T		intron	N/A	ENSP00000405294.1	F8WAX8
	MSH6	ENST00000936511.1		c.3466-16C>T		intron	N/A	ENSP00000606570.1

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 339 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00385

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00210 AC: 527 AN: 251416 AF XY: 0.00211

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00379

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00403 AC: 5811 AN: 1441694 Hom.: 21 Cov.: 27 AF XY: 0.00392 AC XY: 2817 AN XY: 718416

African (AFR) AF: 0.000755 AC: 25 AN: 33104

American (AMR) AF: 0.00154 AC: 69 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.000231 AC: 6 AN: 26002

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 85864

European-Finnish (FIN) AF: 0.000356 AC: 19 AN: 53400

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5736

European-Non Finnish (NFE) AF: 0.00505 AC: 5521 AN: 1093580

Other (OTH) AF: 0.00280 AC: 167 AN: 59698

GnomAD4 genome AF: 0.00223 AC: 339 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.00191 AC XY: 142 AN XY: 74460

African (AFR) AF: 0.00118 AC: 49 AN: 41568

American (AMR) AF: 0.00137 AC: 21 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00385 AC: 262 AN: 68024

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00301 Hom.: 2

Bravo AF: 0.00253

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	4	Lynch syndrome 5 (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	1	1	not provided (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Endometrial carcinoma;C1833477:Lynch syndrome 5;C5436807:Mismatch repair cancer syndrome 3 (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	-0.60
CADD	Benign	15
DANN	Benign	0.91
PhyloP100		0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs192614006; hg19: chr2-48032033; COSMIC: COSV104579293;