NM_014289.4:c.894-15delT

Variant names:

• chrX-111251300-GA-G
• rs201147886
• NM_014289.4:c.894-15delT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_014289.4(CAPN6):​c.894-15delT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0046 (1 hom., 64 hem., cov: 18)
  • Exomes 𝑓: 0.078 (0 hom. 101 hem.)
• Consequence: CAPN6 NM_014289.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant X-111251300-GA-G is Benign according to our data. Variant chrX-111251300-GA-G is described in ClinVar as Benign. ClinVar VariationId is 1221767.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 64 gene

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.894-15delT		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.894-15delT		intron	N/A	ENSP00000317214.1	Q9Y6Q1
	CAPN6	ENST00000932651.1		c.492-15delT		intron	N/A	ENSP00000602710.1

Frequencies

GnomAD3 genomes AF: 0.00458 AC: 392 AN: 85631 Hom.: 1 Cov.: 18

Gnomad AFR AF: 0.00822

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00287

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00872

Gnomad SAS AF: 0.00636

Gnomad FIN AF: 0.00559

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00270

Gnomad OTH AF: 0.000891

GnomAD2 exomes AF: 0.188 AC: 8508 AN: 45184 AF XY: 0.00637

Gnomad AFR exome AF: 0.0630

Gnomad AMR exome AF: 0.188

Gnomad ASJ exome AF: 0.219

Gnomad EAS exome AF: 0.212

Gnomad FIN exome AF: 0.177

Gnomad NFE exome AF: 0.214

Gnomad OTH exome AF: 0.204

GnomAD4 exome AF: 0.0777 AC: 51293 AN: 660164 Hom.: 0 Cov.: 10 AF XY: 0.000599 AC XY: 101 AN XY: 168656

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

African (AFR) AF: 0.0263 AC: 482 AN: 18327

American (AMR) AF: 0.0926 AC: 1602 AN: 17307

Ashkenazi Jewish (ASJ) AF: 0.0825 AC: 943 AN: 11431

East Asian (EAS) AF: 0.0807 AC: 1457 AN: 18044

South Asian (SAS) AF: 0.0626 AC: 1757 AN: 28047

European-Finnish (FIN) AF: 0.0787 AC: 1864 AN: 23682

Middle Eastern (MID) AF: 0.0412 AC: 93 AN: 2255

European-Non Finnish (NFE) AF: 0.0798 AC: 40928 AN: 512861

Other (OTH) AF: 0.0768 AC: 2167 AN: 28210

⚠️ 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: 0.00458 AC: 392 AN: 85628 Hom.: 1 Cov.: 18 AF XY: 0.00314 AC XY: 64 AN XY: 20364

African (AFR) AF: 0.00821 AC: 203 AN: 24723

American (AMR) AF: 0.00274 AC: 21 AN: 7661

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2104

East Asian (EAS) AF: 0.00913 AC: 25 AN: 2739

South Asian (SAS) AF: 0.00641 AC: 12 AN: 1871

European-Finnish (FIN) AF: 0.00559 AC: 18 AN: 3219

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

European-Non Finnish (NFE) AF: 0.00270 AC: 112 AN: 41477

Other (OTH) AF: 0.000881 AC: 1 AN: 1135

Alfa AF: 0.0474 Hom.: 4

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=100/0	polymorphism (auto)

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; COSMIC: COSV60694292;