NM_004924.6:c.2469C>T

Variant names:

• chr19-38729046-C-T
• rs143282009
• NM_004924.6:c.2469C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004924.6(ACTN4):​c.2469C>T​(p.Ser823Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000296 in 1,613,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: ACTN4 NM_004924.6 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.30

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=-0.54).
• BP6: Variant 19-38729046-C-T is Benign according to our data. Variant chr19-38729046-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 585362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.3 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000217 (33/152324) while in subpopulation AMR AF= 0.000457 (7/15308). AF 95% confidence interval is 0.000218. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN4	NM_004924.6	c.2469C>T	p.Ser823Ser	synonymous_variant	Exon 20 of 21	ENST00000252699.7	NP_004915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN4	ENST00000252699.7	c.2469C>T	p.Ser823Ser	synonymous_variant	Exon 20 of 21	1	NM_004924.6	ENSP00000252699.2

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152206 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000319 AC: 80 AN: 250852 Hom.: 0 AF XY: 0.000324 AC XY: 44 AN XY: 135804

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000459

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000304 AC: 444 AN: 1461252 Hom.: 0 Cov.: 33 AF XY: 0.000315 AC XY: 229 AN XY: 726936

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000330

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152324 Hom.: 0 Cov.: 31 AF XY: 0.000215 AC XY: 16 AN XY: 74488

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000474 Hom.: 0

Bravo AF: 0.000378

EpiCase AF: 0.000654

EpiControl AF: 0.000711

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jun 05, 2018

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACTN4: BP4, BP7 -

Focal segmental glomerulosclerosis 1 Benign:1

Feb 03, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	4.0
DANN	Benign	0.92

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: rs143282009; hg19: chr19-39219686; COSMIC: COSV99400157; COSMIC: COSV99400157;