chr19-38724087-C-G

Variant names:

• chr19-38724087-C-G
• rs199619802
• NM_004924.6:c.1692+10C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004924.6(ACTN4):​c.1692+10C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00393 in 1,613,630 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (19 hom.)
• Consequence: ACTN4 NM_004924.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -5.15
• Publications: 0 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 19-38724087-C-G is Benign according to our data. Variant chr19-38724087-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00286 (435/152234) while in subpopulation NFE AF = 0.00515 (350/67992). AF 95% confidence interval is 0.0047. There are 2 homozygotes in GnomAd4. There are 186 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 435 AD gene.

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.1692+10C>G		intron	N/A	NP_004915.2
	ACTN4	NM_001440296.1		c.1692+10C>G		intron	N/A	NP_001427225.1
	ACTN4	NM_001440300.1		c.1692+10C>G		intron	N/A	NP_001427229.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN4	ENST00000252699.7	TSL:1 MANE Select	c.1692+10C>G		intron	N/A	ENSP00000252699.2
	ACTN4	ENST00000424234.7	TSL:1	c.1692+10C>G		intron	N/A	ENSP00000411187.4
	ACTN4	ENST00000390009.7	TSL:1	c.1035+10C>G		intron	N/A	ENSP00000439497.1

Frequencies

GnomAD3 genomes AF: 0.00286 AC: 435 AN: 152118 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000749

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00515

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00231 AC: 579 AN: 250518 AF XY: 0.00227

Gnomad AFR exome AF: 0.000560

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.00455

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00404 AC: 5909 AN: 1461396 Hom.: 19 Cov.: 37 AF XY: 0.00394 AC XY: 2864 AN XY: 727012

African (AFR) AF: 0.000747 AC: 25 AN: 33480

American (AMR) AF: 0.000827 AC: 37 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86258

European-Finnish (FIN) AF: 0.000718 AC: 38 AN: 52938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00506 AC: 5630 AN: 1112000

Other (OTH) AF: 0.00253 AC: 153 AN: 60392

GnomAD4 genome AF: 0.00286 AC: 435 AN: 152234 Hom.: 2 Cov.: 32 AF XY: 0.00250 AC XY: 186 AN XY: 74442

African (AFR) AF: 0.000747 AC: 31 AN: 41518

American (AMR) AF: 0.00170 AC: 26 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00515 AC: 350 AN: 67992

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00283 Hom.: 0

Bravo AF: 0.00277

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Jan 18, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Focal segmental glomerulosclerosis 1 Benign:1

Dec 05, 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	-0.92
CADD	Benign	0.11
DANN	Benign	0.19
PhyloP100		-5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs199619802; hg19: chr19-39214727;