rs17879776

Variant names:

• chrX-111248637-G-A
• rs17879776
• NM_014289.4:c.1416C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_014289.4(CAPN6):​c.1416C>T​(p.Thr472Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,207,994 control chromosomes in the GnomAD database, including 21 homozygotes. There are 417 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0070 (9 hom., 207 hem., cov: 23)
  • Exomes 𝑓: 0.00071 (12 hom. 210 hem.)
• Consequence: CAPN6 NM_014289.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.45
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant X-111248637-G-A is Benign according to our data. Variant chrX-111248637-G-A is described in ClinVar as Benign. ClinVar VariationId is 777822.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.45 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00702 (785/111838) while in subpopulation AFR AF = 0.0244 (751/30785). AF 95% confidence interval is 0.0229. There are 9 homozygotes in GnomAd4. There are 207 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.1416C>T	p.Thr472Thr	synonymous	Exon 10 of 13	NP_055104.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CAPN6	ENST00000324068.2	TSL:1 MANE Select	c.1416C>T	p.Thr472Thr	synonymous	Exon 10 of 13	ENSP00000317214.1	Q9Y6Q1
	CAPN6	ENST00000932651.1		c.1014C>T	p.Thr338Thr	synonymous	Exon 8 of 11	ENSP00000602710.1

Frequencies

GnomAD3 genomes AF: 0.00701 AC: 784 AN: 111785 Hom.: 9 Cov.: 23

Gnomad AFR AF: 0.0244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00218

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: 0.0000188

Gnomad OTH AF: 0.00660

GnomAD2 exomes AF: 0.00177 AC: 325 AN: 183283 AF XY: 0.00109

Gnomad AFR exome AF: 0.0220

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000489

Gnomad OTH exome AF: 0.000884

GnomAD4 exome AF: 0.000709 AC: 777 AN: 1096156 Hom.: 12 Cov.: 30 AF XY: 0.000580 AC XY: 210 AN XY: 362322

African (AFR) AF: 0.0230 AC: 607 AN: 26349

American (AMR) AF: 0.00116 AC: 41 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19377

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

South Asian (SAS) AF: 0.0000370 AC: 2 AN: 54079

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40533

Middle Eastern (MID) AF: 0.00130 AC: 4 AN: 3084

European-Non Finnish (NFE) AF: 0.0000630 AC: 53 AN: 841361

Other (OTH) AF: 0.00152 AC: 70 AN: 45973

GnomAD4 genome AF: 0.00702 AC: 785 AN: 111838 Hom.: 9 Cov.: 23 AF XY: 0.00609 AC XY: 207 AN XY: 34016

African (AFR) AF: 0.0244 AC: 751 AN: 30785

American (AMR) AF: 0.00218 AC: 23 AN: 10568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3536

South Asian (SAS) AF: 0.00 AC: 0 AN: 2608

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6086

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53168

Other (OTH) AF: 0.00652 AC: 10 AN: 1534

Alfa AF: 0.00526 Hom.: 14

Bravo AF: 0.00791

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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
BayesDel_noAF	Benign	-0.40
CADD	Benign	9.1
DANN	Benign	0.65
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs17879776; hg19: chrX-110491865;