chr19-38730655-A-G

Position:

• chr19-38730655-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004924.6(ACTN4):​c.*1223A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.734 in 642,284 control chromosomes in the GnomAD database, including 175,119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (37273 hom., cov: 31)
  • Exomes 𝑓: 0.75 (137846 hom.)
• Consequence: ACTN4 NM_004924.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.50

Genes affected

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: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]

CAPN12 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 19-38730655-A-G is Benign according to our data. Variant chr19-38730655-A-G is described in ClinVar as [Benign]. Clinvar id is 1275240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.821 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTN4	NM_004924.6	c.*1223A>G		3_prime_UTR_variant	21/21	ENST00000252699.7	NP_004915.2
CAPN12	NM_144691.4	c.*197T>C		3_prime_UTR_variant	21/21	ENST00000328867.9	NP_653292.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTN4	ENST00000252699.7	c.*1223A>G		3_prime_UTR_variant	21/21	1	NM_004924.6	ENSP00000252699.2
CAPN12	ENST00000328867	c.*197T>C		3_prime_UTR_variant	21/21	1	NM_144691.4	ENSP00000331636.3

Frequencies

GnomAD3 genomes AF: 0.694 AC: 105428 AN: 151876 Hom.: 37240 Cov.: 31

Gnomad AFR AF: 0.575

Gnomad AMI AF: 0.884

Gnomad AMR AF: 0.663

Gnomad ASJ AF: 0.712

Gnomad EAS AF: 0.639

Gnomad SAS AF: 0.844

Gnomad FIN AF: 0.733

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.757

Gnomad OTH AF: 0.707

GnomAD4 exome AF: 0.747 AC: 366136 AN: 490290 Hom.: 137846 Cov.: 5 AF XY: 0.753 AC XY: 194502 AN XY: 258258

Gnomad4 AFR exome AF: 0.587

Gnomad4 AMR exome AF: 0.621

Gnomad4 ASJ exome AF: 0.711

Gnomad4 EAS exome AF: 0.701

Gnomad4 SAS exome AF: 0.854

Gnomad4 FIN exome AF: 0.733

Gnomad4 NFE exome AF: 0.757

Gnomad4 OTH exome AF: 0.730

GnomAD4 genome AF: 0.694 AC: 105506 AN: 151994 Hom.: 37273 Cov.: 31 AF XY: 0.695 AC XY: 51623 AN XY: 74280

Gnomad4 AFR AF: 0.575

Gnomad4 AMR AF: 0.662

Gnomad4 ASJ AF: 0.712

Gnomad4 EAS AF: 0.639

Gnomad4 SAS AF: 0.843

Gnomad4 FIN AF: 0.733

Gnomad4 NFE AF: 0.757

Gnomad4 OTH AF: 0.710

Alfa AF: 0.734 Hom.: 39622

Bravo AF: 0.679

Asia WGS AF: 0.768 AC: 2669 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.15
DANN	Benign	0.29

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: rs1060186; hg19: chr19-39221295;