19-38724532-T-C

Variant names:

• chr19-38724532-T-C
• rs12986337
• NM_004924.6:c.1977T>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.1977T>C​(p.Asn659Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.065 in 1,613,590 control chromosomes in the GnomAD database, including 3,757 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (265 hom., cov: 32)
  • Exomes 𝑓: 0.066 (3492 hom.)
• Consequence: ACTN4 NM_004924.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.00600
• Publications: 12 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

ENSG00000298338 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 19-38724532-T-C is Benign according to our data. Variant chr19-38724532-T-C is described in ClinVar as Benign. ClinVar VariationId is 259571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.006 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0889 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.1977T>C	p.Asn659Asn	synonymous	Exon 16 of 21	NP_004915.2
	ACTN4	NM_001440296.1		c.1977T>C	p.Asn659Asn	synonymous	Exon 16 of 22	NP_001427225.1
	ACTN4	NM_001440300.1		c.1977T>C	p.Asn659Asn	synonymous	Exon 16 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.1977T>C	p.Asn659Asn	synonymous	Exon 16 of 21	ENSP00000252699.2
	ACTN4	ENST00000424234.7	TSL:1	c.1977T>C	p.Asn659Asn	synonymous	Exon 16 of 21	ENSP00000411187.4
	ACTN4	ENST00000390009.7	TSL:1	c.1320T>C	p.Asn440Asn	synonymous	Exon 9 of 14	ENSP00000439497.1

Frequencies

GnomAD3 genomes AF: 0.0572 AC: 8693 AN: 152084 Hom.: 266 Cov.: 32

Gnomad AFR AF: 0.0502

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0617

Gnomad ASJ AF: 0.0582

Gnomad EAS AF: 0.0460

Gnomad SAS AF: 0.0967

Gnomad FIN AF: 0.0259

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0638

Gnomad OTH AF: 0.0578

GnomAD2 exomes AF: 0.0635 AC: 15909 AN: 250450 AF XY: 0.0651

Gnomad AFR exome AF: 0.0509

Gnomad AMR exome AF: 0.0698

Gnomad ASJ exome AF: 0.0615

Gnomad EAS exome AF: 0.0405

Gnomad FIN exome AF: 0.0279

Gnomad NFE exome AF: 0.0628

Gnomad OTH exome AF: 0.0679

GnomAD4 exome AF: 0.0659 AC: 96234 AN: 1461388 Hom.: 3492 Cov.: 38 AF XY: 0.0668 AC XY: 48593 AN XY: 727006

African (AFR) AF: 0.0518 AC: 1734 AN: 33472

American (AMR) AF: 0.0729 AC: 3258 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0632 AC: 1651 AN: 26128

East Asian (EAS) AF: 0.0457 AC: 1815 AN: 39698

South Asian (SAS) AF: 0.102 AC: 8761 AN: 86254

European-Finnish (FIN) AF: 0.0305 AC: 1616 AN: 53016

Middle Eastern (MID) AF: 0.0687 AC: 396 AN: 5766

European-Non Finnish (NFE) AF: 0.0657 AC: 73010 AN: 1111952

Other (OTH) AF: 0.0661 AC: 3993 AN: 60384

GnomAD4 genome AF: 0.0571 AC: 8697 AN: 152202 Hom.: 265 Cov.: 32 AF XY: 0.0563 AC XY: 4194 AN XY: 74430

African (AFR) AF: 0.0502 AC: 2083 AN: 41522

American (AMR) AF: 0.0615 AC: 942 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0582 AC: 202 AN: 3470

East Asian (EAS) AF: 0.0461 AC: 239 AN: 5180

South Asian (SAS) AF: 0.0961 AC: 464 AN: 4826

European-Finnish (FIN) AF: 0.0259 AC: 274 AN: 10588

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0638 AC: 4341 AN: 67988

Other (OTH) AF: 0.0587 AC: 124 AN: 2114

Alfa AF: 0.0595 Hom.: 116

Bravo AF: 0.0594

Asia WGS AF: 0.0890 AC: 311 AN: 3478

EpiCase AF: 0.0649

EpiControl AF: 0.0670

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Focal segmental glomerulosclerosis 1 Benign:2

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 12, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

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	-0.77
CADD	Benign	6.1
DANN	Benign	0.61
PhyloP100		0.0060
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs12986337; hg19: chr19-39215172; COSMIC: COSV53142966; COSMIC: COSV53142966;