Genetic Variant CAPN6:c.894-16_894-15dupTT (chrX-111251300-G-GAA) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_014289.4(CAPN6):c.894-16_894-15dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., 19 hem., cov: 18)

Exomes 𝑓: 0.0014 ( 0 hom. 2 hem. )

Consequence

CAPN6
NM_014289.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.31

Publications

0 publications found

Variant links:

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]

CAPN6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High Hemizygotes in GnomAd4 at 19 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.894-16_894-15dupTT		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.894-15_894-14insTT		intron	N/A	ENSP00000317214.1	Q9Y6Q1
	CAPN6	ENST00000932651.1		c.492-15_492-14insTT		intron	N/A	ENSP00000602710.1

Frequencies

GnomAD3 genomes

AF:

0.00117

AC:

100

AN:

85806

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00376

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000522

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:

0.0000481

Gnomad OTH

AF:

0.000890

GnomAD2 exomes

AF:

0.00540

AC:

244

AN:

45184

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0321

Gnomad AMR exome

AF:

0.00272

Gnomad ASJ exome

AF:

0.00310

Gnomad EAS exome

AF:

0.000618

Gnomad FIN exome

AF:

0.00232

Gnomad NFE exome

AF:

0.00186

Gnomad OTH exome

AF:

0.00178

GnomAD4 exome

AF:

0.00140

AC:

1161

AN:

831332

Hom.:

Cov.:

AF XY:

0.00000803

AC XY:

AN XY:

249046

show subpopulations

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

African (AFR)

AF:

0.0315

AC:

593

AN:

18833

American (AMR)

AF:

0.00113

AC:

AN:

22169

Ashkenazi Jewish (ASJ)

AF:

0.000786

AC:

AN:

15263

East Asian (EAS)

AF:

0.0000780

AC:

AN:

25655

South Asian (SAS)

AF:

0.000466

AC:

AN:

38594

European-Finnish (FIN)

AF:

0.000270

AC:

AN:

33354

Middle Eastern (MID)

AF:

0.000697

AC:

AN:

2868

European-Non Finnish (NFE)

AF:

0.000661

AC:

422

AN:

638690

Other (OTH)

AF:

0.00217

AC:

AN:

35906

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.267

Heterozygous variant carriers

131

262

392

523

654

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00117

AC:

100

AN:

85804

Hom.:

Cov.:

AF XY:

0.000929

AC XY:

AN XY:

20456

show subpopulations

African (AFR)

AF:

0.00376

AC:

AN:

24736

American (AMR)

AF:

0.000521

AC:

AN:

7672

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2111

East Asian (EAS)

AF:

0.00

AC:

AN:

2741

South Asian (SAS)

AF:

0.00

AC:

AN:

1872

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3277

Middle Eastern (MID)

AF:

0.00

AC:

AN:

172

European-Non Finnish (NFE)

AF:

0.0000481

AC:

AN:

41559

Other (OTH)

AF:

0.000880

AC:

AN:

1137

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00189

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.3

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over