X-111251300-GAAA-GA

Variant names:

• chrX-111251300-GAA-G
• rs201147886
• NM_014289.4:c.894-16_894-15delTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_014289.4(CAPN6):​c.894-16_894-15delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000439 in 914,379 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000012 (0 hom., 0 hem., cov: 18)
  • Exomes 𝑓: 0.00048 (0 hom. 1 hem.)
• Consequence: CAPN6 NM_014289.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.31
• Publications: 0 publications found

Genes affected

CAPN6 (HGNC:1483): (calpain 6) Calpains are ubiquitous, well-conserved family of calcium-dependent, cysteine proteases. The calpain proteins are heterodimers consisting of an invariant small subunit and variable large subunits. The large subunit possesses a cysteine protease domain, and both subunits possess calcium-binding domains. Calpains have been implicated in neurodegenerative processes, as their activation can be triggered by calcium influx and oxidative stress. The protein encoded by this gene is highly expressed in the placenta. Its C-terminal region lacks any homology to the calmodulin-like domain of other calpains. The protein lacks critical active site residues and thus is suggested to be proteolytically inactive. The protein may play a role in tumor formation by inhibiting apoptosis and promoting angiogenesis. [provided by RefSeq, Nov 2009]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014289.4. 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
	CAPN6	NM_014289.4	MANE Select	c.894-16_894-15delTT		intron	N/A	NP_055104.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN6	ENST00000324068.2	TSL:1 MANE Select	c.894-16_894-15delTT		intron	N/A	ENSP00000317214.1	Q9Y6Q1
	CAPN6	ENST00000932651.1		c.492-16_492-15delTT		intron	N/A	ENSP00000602710.1

Frequencies

GnomAD3 genomes AF: 0.0000117 AC: 1 AN: 85791 Hom.: 0 Cov.: 18

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00206 AC: 93 AN: 45184 AF XY: 0.000490

Gnomad AFR exome AF: 0.000384

Gnomad AMR exome AF: 0.00200

Gnomad ASJ exome AF: 0.00310

Gnomad EAS exome AF: 0.00155

Gnomad FIN exome AF: 0.00256

Gnomad NFE exome AF: 0.00248

Gnomad OTH exome AF: 0.00178

GnomAD4 exome AF: 0.000483 AC: 400 AN: 828590 Hom.: 0 AF XY: 0.00000404 AC XY: 1 AN XY: 247800

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

African (AFR) AF: 0.000251 AC: 5 AN: 19954

American (AMR) AF: 0.000950 AC: 21 AN: 22102

Ashkenazi Jewish (ASJ) AF: 0.000660 AC: 10 AN: 15145

East Asian (EAS) AF: 0.000274 AC: 7 AN: 25506

South Asian (SAS) AF: 0.000418 AC: 16 AN: 38238

European-Finnish (FIN) AF: 0.000211 AC: 7 AN: 33116

Middle Eastern (MID) AF: 0.000349 AC: 1 AN: 2865

European-Non Finnish (NFE) AF: 0.000506 AC: 322 AN: 635795

Other (OTH) AF: 0.000307 AC: 11 AN: 35869

⚠️ 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: 0.0000117 AC: 1 AN: 85789 Hom.: 0 Cov.: 18 AF XY: 0.00 AC XY: 0 AN XY: 20455

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

African (AFR) AF: 0.00 AC: 0 AN: 24736

American (AMR) AF: 0.000130 AC: 1 AN: 7671

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2111

East Asian (EAS) AF: 0.00 AC: 0 AN: 2741

South Asian (SAS) AF: 0.00 AC: 0 AN: 1872

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3271

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 172

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 41551

Other (OTH) AF: 0.00 AC: 0 AN: 1137

⚠️ 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: 0.00353 Hom.: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
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: rs201147886; hg19: chrX-110494528;