19-38731307-A-T

Position:

• chr19-38731307-A-T

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.*1875A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 1,034,664 control chromosomes in the GnomAD database, including 28,176 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4162 hom., cov: 32)
  • Exomes 𝑓: 0.23 (24014 hom.)
• Consequence: ACTN4 NM_004924.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.68

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=-0.89).
• BP6: Variant 19-38731307-A-T is Benign according to our data. Variant chr19-38731307-A-T is described in ClinVar as [Benign]. Clinvar id is 1293783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.352 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTN4	NM_004924.6	c.*1875A>T		3_prime_UTR_variant	21/21	ENST00000252699.7	NP_004915.2
CAPN12	NM_144691.4	c.1958-84T>A		intron_variant		ENST00000328867.9	NP_653292.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTN4	ENST00000252699.7	c.*1875A>T		3_prime_UTR_variant	21/21	1	NM_004924.6	ENSP00000252699.2
CAPN12	ENST00000328867.9	c.1958-84T>A		intron_variant		1	NM_144691.4	ENSP00000331636.3

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34514 AN: 151824 Hom.: 4146 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.240

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.366

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.382

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.261

GnomAD4 exome AF: 0.227 AC: 200194 AN: 882722 Hom.: 24014 Cov.: 12 AF XY: 0.233 AC XY: 107087 AN XY: 459652

Gnomad4 AFR exome AF: 0.244

Gnomad4 AMR exome AF: 0.245

Gnomad4 ASJ exome AF: 0.252

Gnomad4 EAS exome AF: 0.126

Gnomad4 SAS exome AF: 0.351

Gnomad4 FIN exome AF: 0.217

Gnomad4 NFE exome AF: 0.215

Gnomad4 OTH exome AF: 0.230

GnomAD4 genome AF: 0.228 AC: 34584 AN: 151942 Hom.: 4162 Cov.: 32 AF XY: 0.230 AC XY: 17046 AN XY: 74272

Gnomad4 AFR AF: 0.233

Gnomad4 AMR AF: 0.240

Gnomad4 ASJ AF: 0.247

Gnomad4 EAS AF: 0.144

Gnomad4 SAS AF: 0.366

Gnomad4 FIN AF: 0.202

Gnomad4 NFE AF: 0.217

Gnomad4 OTH AF: 0.267

Alfa AF: 0.221 Hom.: 476

Bravo AF: 0.228

Asia WGS AF: 0.333 AC: 1154 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	-0.89
CADD	Benign	0.22
DANN	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs4801859; hg19: chr19-39221947;