2-47806770-A-T

Variant names:

• chr2-47806770-A-T
• rs755141440
• NM_000179.3:c.4002-9A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000179.3(MSH6):​c.4002-9A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene MSH6 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00080 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH6 NM_000179.3 intron
• Scores: Splicing: ADA: 0.00001722
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.655
• Publications: 0 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-47806770-A-T is Benign according to our data. Variant chr2-47806770-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 378173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.4002-9A>T		intron	N/A	NP_000170.1	P52701-1
	MSH6	NM_001406795.1		c.4098-9A>T		intron	N/A	NP_001393724.1
	MSH6	NM_001406813.1		c.4008-9A>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.4002-9A>T		intron	N/A	ENSP00000234420.5	P52701-1
	MSH6	ENST00000445503.5	TSL:1	n.*3349-9A>T		intron	N/A	ENSP00000405294.1	F8WAX8
	MSH6	ENST00000936511.1		c.4029-9A>T		intron	N/A	ENSP00000606570.1

Frequencies

GnomAD3 genomes AF: 0.000824 AC: 108 AN: 131012 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000232

Gnomad FIN AF: 0.00526

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000903

Gnomad OTH AF: 0.000555

GnomAD2 exomes AF: 0.00431 AC: 841 AN: 195286 AF XY: 0.00453

Gnomad AFR exome AF: 0.00139

Gnomad AMR exome AF: 0.00464

Gnomad ASJ exome AF: 0.00337

Gnomad EAS exome AF: 0.00194

Gnomad FIN exome AF: 0.00185

Gnomad NFE exome AF: 0.00398

Gnomad OTH exome AF: 0.00570

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000800 AC: 1073 AN: 1341324 Hom.: 0 Cov.: 31 AF XY: 0.000856 AC XY: 573 AN XY: 669248

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00171 AC: 48 AN: 28072

American (AMR) AF: 0.00835 AC: 298 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 30 AN: 24562

East Asian (EAS) AF: 0.0000789 AC: 3 AN: 38014

South Asian (SAS) AF: 0.00337 AC: 260 AN: 77208

European-Finnish (FIN) AF: 0.000476 AC: 22 AN: 46196

Middle Eastern (MID) AF: 0.000939 AC: 5 AN: 5326

European-Non Finnish (NFE) AF: 0.000350 AC: 361 AN: 1030314

Other (OTH) AF: 0.000822 AC: 46 AN: 55928

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000824 AC: 108 AN: 131012 Hom.: 0 Cov.: 30 AF XY: 0.000833 AC XY: 53 AN XY: 63606

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000241 AC: 8 AN: 33250

American (AMR) AF: 0.00 AC: 0 AN: 13408

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3204

East Asian (EAS) AF: 0.00 AC: 0 AN: 4814

South Asian (SAS) AF: 0.000232 AC: 1 AN: 4318

European-Finnish (FIN) AF: 0.00526 AC: 43 AN: 8176

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

European-Non Finnish (NFE) AF: 0.000903 AC: 55 AN: 60906

Other (OTH) AF: 0.000555 AC: 1 AN: 1802

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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	-0.87
CADD	Benign	3.6
DANN	Benign	0.51
PhyloP100		-0.66
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.028
SpliceAI score (max)		0.050		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: rs755141440; hg19: chr2-48033909; COSMIC: COSV52287586; COSMIC: COSV52287586;