19-38731021-G-A

Position:

• chr19-38731021-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144691.4(CAPN12):​c.2077C>T​(p.His693Tyr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000285 in 1,402,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: CAPN12 NM_144691.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.47

Genes affected

CAPN12 (HGNC:13249): (calpain 12) The calpains, calcium-activated neutral proteases, are nonlysosomal, intracellular cysteine proteases. The mammalian calpains include ubiquitous, stomach-specific, and muscle-specific proteins. The ubiquitous enzymes consist of heterodimers with distinct large, catalytic subunits associated with a common small, regulatory subunit. This gene encodes a member of the calpain large subunit family. [provided by RefSeq, Jun 2012]

ACTN4 (HGNC:166): (actinin alpha 4) Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of cytoskeletal proteins, including the alpha and beta spectrins and dystrophins. Alpha actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane. In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. This gene encodes a nonmuscle, alpha actinin isoform which is concentrated in the cytoplasm, and thought to be involved in metastatic processes. Mutations in this gene have been associated with focal and segmental glomerulosclerosis. [provided by RefSeq, Jul 2008]

CAPN12 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10303533).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN12	NM_144691.4	c.2077C>T	p.His693Tyr	missense_variant, splice_region_variant	20/21	ENST00000328867.9	NP_653292.2
ACTN4	NM_004924.6	c.*1589G>A		3_prime_UTR_variant	21/21	ENST00000252699.7	NP_004915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN12	ENST00000328867.9	c.2077C>T	p.His693Tyr	missense_variant, splice_region_variant	20/21	1	NM_144691.4	ENSP00000331636.3
ACTN4	ENST00000252699.7	c.*1589G>A		3_prime_UTR_variant	21/21	1	NM_004924.6	ENSP00000252699.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000285 AC: 4 AN: 1402018 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 691944

Gnomad4 AFR exome AF: 0.0000314

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000251

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000172

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2023

The c.2077C>T (p.H693Y) alteration is located in exon 20 (coding exon 20) of the CAPN12 gene. This alteration results from a C to T substitution at nucleotide position 2077, causing the histidine (H) at amino acid position 693 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Benign	0.88
DEOGEN2	Benign	0.014	.;.;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.61	T;.;T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.61	.;.;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.93	.;.;N
REVEL	Benign	0.085
Sift	Benign	1.0	.;.;T
Sift4G	Benign	0.35	T;T;T
Polyphen		0.0010	.;.;B
Vest4		0.38
MutPred		0.51		.;.;Gain of stability (P = 0.2417);
MVP		0.25
MPC		0.069
ClinPred		0.15	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.075
gMVP		0.24

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

Publications

LitVar

Other links and lift over

dbSNP: rs1424777612; hg19: chr19-39221661;