chr2-47806751-CTTTT-C

Variant names:

• chr2-47806751-CTTTT-C
• rs59056100
• NM_000179.3:c.4002-13_4002-10delTTTT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_000179.3(MSH6):​c.4002-13_4002-10delTTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000251 in 1,444,038 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000029 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: MSH6 NM_000179.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.166
• 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

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 2-47806751-CTTTT-C is Benign according to our data. Variant chr2-47806751-CTTTT-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1802702.

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.4002-13_4002-10delTTTT		intron	N/A	NP_000170.1	P52701-1
	MSH6	NM_001406795.1		c.4098-13_4098-10delTTTT		intron	N/A	NP_001393724.1
	MSH6	NM_001406813.1		c.4008-13_4008-10delTTTT		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.4002-13_4002-10delTTTT		intron	N/A	ENSP00000234420.5	P52701-1
	MSH6	ENST00000445503.5	TSL:1	n.*3349-13_*3349-10delTTTT		intron	N/A	ENSP00000405294.1	F8WAX8
	MSH6	ENST00000936511.1		c.4029-13_4029-10delTTTT		intron	N/A	ENSP00000606570.1

Frequencies

GnomAD3 genomes AF: 0.0000289 AC: 4 AN: 138394 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000527

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000235

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000157

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000275 AC: 359 AN: 1305644 Hom.: 0 AF XY: 0.000268 AC XY: 175 AN XY: 651888

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

African (AFR) AF: 0.00214 AC: 60 AN: 28056

American (AMR) AF: 0.000467 AC: 17 AN: 36408

Ashkenazi Jewish (ASJ) AF: 0.000206 AC: 5 AN: 24232

East Asian (EAS) AF: 0.0000289 AC: 1 AN: 34562

South Asian (SAS) AF: 0.000290 AC: 22 AN: 75944

European-Finnish (FIN) AF: 0.000327 AC: 14 AN: 42854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5176

European-Non Finnish (NFE) AF: 0.000227 AC: 228 AN: 1004182

Other (OTH) AF: 0.000221 AC: 12 AN: 54230

⚠️ 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 AF: 0.0000289 AC: 4 AN: 138394 Hom.: 0 Cov.: 0 AF XY: 0.0000449 AC XY: 3 AN XY: 66768

African (AFR) AF: 0.0000527 AC: 2 AN: 37976

American (AMR) AF: 0.00 AC: 0 AN: 13576

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3320

East Asian (EAS) AF: 0.00 AC: 0 AN: 4420

South Asian (SAS) AF: 0.000235 AC: 1 AN: 4248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7960

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 296

European-Non Finnish (NFE) AF: 0.0000157 AC: 1 AN: 63842

Other (OTH) AF: 0.00 AC: 0 AN: 1886

Alfa AF: 0.00 Hom.: 174

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Breast and/or ovarian cancer (1)
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.17
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: rs59056100; hg19: chr2-48033890;