chr19-38729140-T-C

Variant names:

• chr19-38729140-T-C
• rs1136956
• NM_004924.6:c.2563T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004924.6(ACTN4):​c.2563T>C​(p.Leu855Leu) 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 NM_004924.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.25
• Publications: 24 publications found

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]

ACTN4 Gene-Disease associations (from GenCC):

• focal segmental glomerulosclerosis 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 259576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004924.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN4	NM_004924.6	MANE Select	c.2563T>C	p.Leu855Leu	synonymous	Exon 20 of 21	NP_004915.2
	ACTN4	NM_001440296.1		c.2629T>C	p.Leu877Leu	synonymous	Exon 21 of 22	NP_001427225.1
	ACTN4	NM_001440300.1		c.2629T>C	p.Leu877Leu	synonymous	Exon 21 of 22	NP_001427229.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN4	ENST00000252699.7	TSL:1 MANE Select	c.2563T>C	p.Leu855Leu	synonymous	Exon 20 of 21	ENSP00000252699.2
	ACTN4	ENST00000424234.7	TSL:1	c.2563T>C	p.Leu855Leu	synonymous	Exon 20 of 21	ENSP00000411187.4
	ACTN4	ENST00000390009.7	TSL:1	c.1906T>C	p.Leu636Leu	synonymous	Exon 13 of 14	ENSP00000439497.1

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

GnomAD2 exomes AF: 0.222 AC: 55596 AN: 250552 AF XY: 0.229

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 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

African (AFR) AF: 0.139 AC: 4640 AN: 33480

American (AMR) AF: 0.186 AC: 8301 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.280 AC: 7319 AN: 26136

East Asian (EAS) AF: 0.0481 AC: 1908 AN: 39700

South Asian (SAS) AF: 0.267 AC: 23059 AN: 86256

European-Finnish (FIN) AF: 0.194 AC: 10183 AN: 52504

Middle Eastern (MID) AF: 0.394 AC: 2271 AN: 5768

European-Non Finnish (NFE) AF: 0.249 AC: 276454 AN: 1111994

Other (OTH) AF: 0.235 AC: 14174 AN: 60388

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

African (AFR) AF: 0.136 AC: 5647 AN: 41396

American (AMR) AF: 0.222 AC: 3390 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 952 AN: 3466

East Asian (EAS) AF: 0.0541 AC: 279 AN: 5154

South Asian (SAS) AF: 0.257 AC: 1232 AN: 4786

European-Finnish (FIN) AF: 0.186 AC: 1964 AN: 10558

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.256 AC: 17366 AN: 67882

Other (OTH) AF: 0.242 AC: 509 AN: 2102

Alfa AF: 0.240 Hom.: 2310

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

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:2

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Focal segmental glomerulosclerosis 1 Benign:2

Apr 12, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	7.3
DANN	Benign	0.85
PhyloP100		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

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