NM_014289.4:c.1743+105G>A

Variant names:

• chrX-111247263-C-T
• rs2404703
• NM_014289.4:c.1743+105G>A

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.1743+105G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0558 in 752,322 control chromosomes in the GnomAD database, including 3,934 homozygotes. There are 10,383 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2274 hom., 4018 hem., cov: 21)
  • Exomes 𝑓: 0.041 (1660 hom. 6365 hem.)
• Consequence: CAPN6 NM_014289.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.761
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant X-111247263-C-T is Benign according to our data. Variant chrX-111247263-C-T is described in ClinVar as Benign. ClinVar VariationId is 1179669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.436 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.1743+105G>A		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.1743+105G>A		intron	N/A	ENSP00000317214.1	Q9Y6Q1
	CAPN6	ENST00000932651.1		c.1341+105G>A		intron	N/A	ENSP00000602710.1

Frequencies

GnomAD3 genomes AF: 0.146 AC: 15810 AN: 108599 Hom.: 2273 Cov.: 21

Gnomad AFR AF: 0.442

Gnomad AMI AF: 0.00593

Gnomad AMR AF: 0.0794

Gnomad ASJ AF: 0.0192

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.00972

Gnomad FIN AF: 0.0123

Gnomad MID AF: 0.113

Gnomad NFE AF: 0.0307

Gnomad OTH AF: 0.131

GnomAD4 exome AF: 0.0406 AC: 26147 AN: 643675 Hom.: 1660 AF XY: 0.0407 AC XY: 6365 AN XY: 156251

African (AFR) AF: 0.458 AC: 7376 AN: 16091

American (AMR) AF: 0.0499 AC: 986 AN: 19741

Ashkenazi Jewish (ASJ) AF: 0.0224 AC: 256 AN: 11444

East Asian (EAS) AF: 0.000531 AC: 14 AN: 26376

South Asian (SAS) AF: 0.00964 AC: 205 AN: 21274

European-Finnish (FIN) AF: 0.0152 AC: 507 AN: 33375

Middle Eastern (MID) AF: 0.0846 AC: 203 AN: 2399

European-Non Finnish (NFE) AF: 0.0306 AC: 14779 AN: 483413

Other (OTH) AF: 0.0616 AC: 1821 AN: 29562

GnomAD4 genome AF: 0.146 AC: 15841 AN: 108647 Hom.: 2274 Cov.: 21 AF XY: 0.129 AC XY: 4018 AN XY: 31173

African (AFR) AF: 0.442 AC: 13076 AN: 29593

American (AMR) AF: 0.0792 AC: 787 AN: 9932

Ashkenazi Jewish (ASJ) AF: 0.0192 AC: 50 AN: 2598

East Asian (EAS) AF: 0.00115 AC: 4 AN: 3475

South Asian (SAS) AF: 0.00895 AC: 22 AN: 2459

European-Finnish (FIN) AF: 0.0123 AC: 70 AN: 5708

Middle Eastern (MID) AF: 0.115 AC: 25 AN: 217

European-Non Finnish (NFE) AF: 0.0307 AC: 1614 AN: 52521

Other (OTH) AF: 0.129 AC: 189 AN: 1469

Alfa AF: 0.0448 Hom.: 258

Bravo AF: 0.166

ClinVar

ClinVar submissions

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	-0.88
CADD	Benign	0.40
DANN	Benign	0.51
PhyloP100		-0.76
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: rs2404703; hg19: chrX-110490491;