rs2306196

chr19-38714375-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004924.6(ACTN4):c.820-94C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0479 in 1,145,718 control chromosomes in the GnomAD database, including 1,546 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (161 hom., cov: 33)
  • Exomes 𝑓: 0.049 (1385 hom.)
• Consequence: ACTN4 NM_004924.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.960

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]

LOC107985291 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 19-38714375-C-T is Benign according to our data. Variant chr19-38714375-C-T is described in ClinVar as [Benign]. Clinvar id is 1182437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0547 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN4	NM_004924.6	c.820-94C>T		intron_variant		ENST00000252699.7
LOC107985291	XR_001753937.2	n.170-12211G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN4	ENST00000252699.7	c.820-94C>T		intron_variant		1	NM_004924.6	A1

Frequencies

GnomAD3 genomes AF: 0.0389 AC: 5922 AN: 152142 Hom.: 161 Cov.: 33

Gnomad AFR AF: 0.00888

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.0290

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.0300

Gnomad SAS AF: 0.0337

Gnomad FIN AF: 0.0708

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0562

Gnomad OTH AF: 0.0383

GnomAD4 exome AF: 0.0493 AC: 49011 AN: 993458 Hom.: 1385 AF XY: 0.0482 AC XY: 24605 AN XY: 510416

Gnomad4 AFR exome AF: 0.00718

Gnomad4 AMR exome AF: 0.0248

Gnomad4 ASJ exome AF: 0.0128

Gnomad4 EAS exome AF: 0.0377

Gnomad4 SAS exome AF: 0.0344

Gnomad4 FIN exome AF: 0.0641

Gnomad4 NFE exome AF: 0.0547

Gnomad4 OTH exome AF: 0.0478

GnomAD4 genome AF: 0.0389 AC: 5918 AN: 152260 Hom.: 161 Cov.: 33 AF XY: 0.0393 AC XY: 2924 AN XY: 74452

Gnomad4 AFR AF: 0.00886

Gnomad4 AMR AF: 0.0290

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.0299

Gnomad4 SAS AF: 0.0335

Gnomad4 FIN AF: 0.0708

Gnomad4 NFE AF: 0.0561

Gnomad4 OTH AF: 0.0379

Alfa AF: 0.0493 Hom.: 48

Bravo AF: 0.0339

Asia WGS AF: 0.0420 AC: 146 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 10, 2018

- -

Focal segmental glomerulosclerosis 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	5.3
Dann	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2306196; hg19: chr19-39205015; COSMIC: COSV53147653; COSMIC: COSV53147653;