rs1136956

Positions:

• chr19-38729140-T-C

Variant summary

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

The ENST00000252699.7(ACTN4):​c.2563T>C​(p.Leu855=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,612,768 control chromosomes in the GnomAD database, including 46,915 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3686 hom., cov: 30)
  • Exomes 𝑓: 0.24 (43229 hom.)
• Consequence: ACTN4 ENST00000252699.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.25

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=-0.66).
• BP6: Variant 19-38729140-T-C is Benign according to our data. Variant chr19-38729140-T-C is described in ClinVar as [Benign]. Clinvar id is 259576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38729140-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.25 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTN4	NM_004924.6	c.2563T>C	p.Leu855=	synonymous_variant	20/21	ENST00000252699.7	NP_004915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTN4	ENST00000252699.7	c.2563T>C	p.Leu855=	synonymous_variant	20/21	1	NM_004924.6	ENSP00000252699	A1

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31784 AN: 151702 Hom.: 3686 Cov.: 30

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.361

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.275

Gnomad EAS AF: 0.0540

Gnomad SAS AF: 0.259

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.242

GnomAD3 exomes AF: 0.222 AC: 55596 AN: 250552 Hom.: 6884 AF XY: 0.229 AC XY: 31137 AN XY: 135766

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.176

Gnomad ASJ exome AF: 0.278

Gnomad EAS exome AF: 0.0444

Gnomad SAS exome AF: 0.269

Gnomad FIN exome AF: 0.194

Gnomad NFE exome AF: 0.262

Gnomad OTH exome AF: 0.264

GnomAD4 exome AF: 0.238 AC: 348309 AN: 1460948 Hom.: 43229 Cov.: 47 AF XY: 0.241 AC XY: 175116 AN XY: 726774

Gnomad4 AFR exome AF: 0.139

Gnomad4 AMR exome AF: 0.186

Gnomad4 ASJ exome AF: 0.280

Gnomad4 EAS exome AF: 0.0481

Gnomad4 SAS exome AF: 0.267

Gnomad4 FIN exome AF: 0.194

Gnomad4 NFE exome AF: 0.249

Gnomad4 OTH exome AF: 0.235

GnomAD4 genome AF: 0.209 AC: 31798 AN: 151820 Hom.: 3686 Cov.: 30 AF XY: 0.207 AC XY: 15368 AN XY: 74194

Gnomad4 AFR AF: 0.136

Gnomad4 AMR AF: 0.222

Gnomad4 ASJ AF: 0.275

Gnomad4 EAS AF: 0.0541

Gnomad4 SAS AF: 0.257

Gnomad4 FIN AF: 0.186

Gnomad4 NFE AF: 0.256

Gnomad4 OTH AF: 0.242

Alfa AF: 0.241 Hom.: 2300

Bravo AF: 0.208

Asia WGS AF: 0.178 AC: 621 AN: 3478

EpiCase AF: 0.278

EpiControl AF: 0.277

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 40% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 37. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Focal segmental glomerulosclerosis 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 12, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	7.3
DANN	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1136956; hg19: chr19-39219780; COSMIC: COSV53144374; COSMIC: COSV53144374;