19-38700683-C-T

Position:

• chr19-38700683-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004924.6(ACTN4):​c.246C>T​(p.Leu82=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0268 in 1,614,060 control chromosomes in the GnomAD database, including 1,005 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (85 hom., cov: 32)
  • Exomes 𝑓: 0.027 (920 hom.)
• Consequence: ACTN4 NM_004924.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.701

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 19-38700683-C-T is Benign according to our data. Variant chr19-38700683-C-T is described in ClinVar as [Benign]. Clinvar id is 259575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38700683-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.701 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTN4	NM_004924.6	c.246C>T	p.Leu82=	synonymous_variant	2/21	ENST00000252699.7	NP_004915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTN4	ENST00000252699.7	c.246C>T	p.Leu82=	synonymous_variant	2/21	1	NM_004924.6	ENSP00000252699	A1

Frequencies

GnomAD3 genomes AF: 0.0256 AC: 3892 AN: 152192 Hom.: 84 Cov.: 32

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0601

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0313

Gnomad FIN AF: 0.0382

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0238

Gnomad OTH AF: 0.0283

GnomAD3 exomes AF: 0.0405 AC: 10182 AN: 251356 Hom.: 491 AF XY: 0.0376 AC XY: 5112 AN XY: 135872

Gnomad AFR exome AF: 0.0145

Gnomad AMR exome AF: 0.137

Gnomad ASJ exome AF: 0.0265

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.0331

Gnomad FIN exome AF: 0.0489

Gnomad NFE exome AF: 0.0233

Gnomad OTH exome AF: 0.0370

GnomAD4 exome AF: 0.0269 AC: 39300 AN: 1461750 Hom.: 920 Cov.: 32 AF XY: 0.0269 AC XY: 19587 AN XY: 727198

Gnomad4 AFR exome AF: 0.0174

Gnomad4 AMR exome AF: 0.122

Gnomad4 ASJ exome AF: 0.0247

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0344

Gnomad4 FIN exome AF: 0.0498

Gnomad4 NFE exome AF: 0.0227

Gnomad4 OTH exome AF: 0.0251

GnomAD4 genome AF: 0.0257 AC: 3911 AN: 152310 Hom.: 85 Cov.: 32 AF XY: 0.0266 AC XY: 1984 AN XY: 74470

Gnomad4 AFR AF: 0.0158

Gnomad4 AMR AF: 0.0605

Gnomad4 ASJ AF: 0.0225

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0321

Gnomad4 FIN AF: 0.0382

Gnomad4 NFE AF: 0.0238

Gnomad4 OTH AF: 0.0280

Alfa AF: 0.0239 Hom.: 39

Bravo AF: 0.0288

Asia WGS AF: 0.0160 AC: 54 AN: 3478

EpiCase AF: 0.0242

EpiControl AF: 0.0216

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Focal segmental glomerulosclerosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 20, 2022

- -

Focal segmental glomerulosclerosis 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	7.2
DANN	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs77307137; hg19: chr19-39191323;