19-38700683-C-T

Variant names:

• chr19-38700683-C-T
• rs77307137
• NM_004924.6:c.246C>T

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.246C>T​(p.Leu82Leu) 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
• Publications: 4 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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=-0.6).
• BP6: Variant 19-38700683-C-T is Benign according to our data. Variant chr19-38700683-C-T is described in ClinVar as Benign. ClinVar VariationId is 259575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN4	NM_004924.6	MANE Select	c.246C>T	p.Leu82Leu	synonymous	Exon 2 of 21	NP_004915.2
	ACTN4	NM_001440296.1		c.246C>T	p.Leu82Leu	synonymous	Exon 2 of 22	NP_001427225.1
	ACTN4	NM_001440300.1		c.246C>T	p.Leu82Leu	synonymous	Exon 2 of 22	NP_001427229.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN4	ENST00000252699.7	TSL:1 MANE Select	c.246C>T	p.Leu82Leu	synonymous	Exon 2 of 21	ENSP00000252699.2	O43707-1
	ACTN4	ENST00000424234.7	TSL:1	c.246C>T	p.Leu82Leu	synonymous	Exon 2 of 21	ENSP00000411187.4	F5GXS2
	ACTN4	ENST00000390009.7	TSL:1	c.163-13786C>T		intron	N/A	ENSP00000439497.1	O43707-2

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

GnomAD2 exomes AF: 0.0405 AC: 10182 AN: 251356 AF XY: 0.0376

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 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

African (AFR) AF: 0.0174 AC: 582 AN: 33480

American (AMR) AF: 0.122 AC: 5470 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0247 AC: 645 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.0344 AC: 2969 AN: 86258

European-Finnish (FIN) AF: 0.0498 AC: 2660 AN: 53362

Middle Eastern (MID) AF: 0.0316 AC: 182 AN: 5766

European-Non Finnish (NFE) AF: 0.0227 AC: 25273 AN: 1111932

Other (OTH) AF: 0.0251 AC: 1513 AN: 60394

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

African (AFR) AF: 0.0158 AC: 657 AN: 41574

American (AMR) AF: 0.0605 AC: 926 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 78 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.0321 AC: 155 AN: 4824

European-Finnish (FIN) AF: 0.0382 AC: 406 AN: 10618

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0238 AC: 1616 AN: 68014

Other (OTH) AF: 0.0280 AC: 59 AN: 2108

Alfa AF: 0.0240 Hom.: 40

Bravo AF: 0.0288

Asia WGS AF: 0.0160 AC: 54 AN: 3478

EpiCase AF: 0.0242

EpiControl AF: 0.0216

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Focal segmental glomerulosclerosis (1)
-	-	1	Focal segmental glomerulosclerosis 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	7.2
DANN	Benign	0.88
PhyloP100		-0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=99/1	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: rs77307137; hg19: chr19-39191323;