rs926412

Variant names:

• chrX-111250789-T-A
• rs926412
• NM_014289.4:c.1158+128A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014289.4(CAPN6):​c.1158+128A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0276 in 633,511 control chromosomes in the GnomAD database, including 1,577 homozygotes. There are 4,628 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (1024 hom., 2592 hem., cov: 22)
  • Exomes 𝑓: 0.015 (553 hom. 2036 hem.)
• Consequence: CAPN6 NM_014289.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.207
• Publications: 1 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant X-111250789-T-A is Benign according to our data. Variant chrX-111250789-T-A is described in ClinVar as Benign. ClinVar VariationId is 1225678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

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.1158+128A>T		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.1158+128A>T		intron	N/A	ENSP00000317214.1	Q9Y6Q1
	CAPN6	ENST00000932651.1		c.756+128A>T		intron	N/A	ENSP00000602710.1

Frequencies

GnomAD3 genomes AF: 0.0879 AC: 9816 AN: 111705 Hom.: 1024 Cov.: 22

Gnomad AFR AF: 0.291

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0484

Gnomad ASJ AF: 0.00756

Gnomad EAS AF: 0.000279

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000652

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.00580

Gnomad OTH AF: 0.0657

GnomAD4 exome AF: 0.0147 AC: 7688 AN: 521754 Hom.: 553 AF XY: 0.0136 AC XY: 2036 AN XY: 149718

African (AFR) AF: 0.306 AC: 4299 AN: 14048

American (AMR) AF: 0.0257 AC: 571 AN: 22194

Ashkenazi Jewish (ASJ) AF: 0.00643 AC: 75 AN: 11666

East Asian (EAS) AF: 0.0000367 AC: 1 AN: 27222

South Asian (SAS) AF: 0.00333 AC: 99 AN: 29726

European-Finnish (FIN) AF: 0.00120 AC: 44 AN: 36688

Middle Eastern (MID) AF: 0.0266 AC: 75 AN: 2823

European-Non Finnish (NFE) AF: 0.00498 AC: 1750 AN: 351231

Other (OTH) AF: 0.0296 AC: 774 AN: 26156

GnomAD4 genome AF: 0.0879 AC: 9826 AN: 111757 Hom.: 1024 Cov.: 22 AF XY: 0.0763 AC XY: 2592 AN XY: 33979

African (AFR) AF: 0.290 AC: 8871 AN: 30540

American (AMR) AF: 0.0483 AC: 509 AN: 10540

Ashkenazi Jewish (ASJ) AF: 0.00756 AC: 20 AN: 2646

East Asian (EAS) AF: 0.000280 AC: 1 AN: 3571

South Asian (SAS) AF: 0.00112 AC: 3 AN: 2681

European-Finnish (FIN) AF: 0.000652 AC: 4 AN: 6134

Middle Eastern (MID) AF: 0.0509 AC: 11 AN: 216

European-Non Finnish (NFE) AF: 0.00580 AC: 309 AN: 53232

Other (OTH) AF: 0.0649 AC: 98 AN: 1511

Alfa AF: 0.0555 Hom.: 295

Bravo AF: 0.104

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.9
DANN	Benign	0.55
PhyloP100		0.21
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: rs926412; hg19: chrX-110494017;