rs2306196

Variant names:

• chr19-38714375-C-T
• rs2306196
• NM_004924.6:c.820-94C>T

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: -0.960
• Publications: 2 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=-0.71).
• BP6: Variant 19-38714375-C-T is Benign according to our data. Variant chr19-38714375-C-T is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
ACTN4	NM_004924.6	c.820-94C>T		intron_variant	Intron 8 of 20	ENST00000252699.7	NP_004915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN4	ENST00000252699.7	c.820-94C>T		intron_variant	Intron 8 of 20	1	NM_004924.6	ENSP00000252699.2

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

African (AFR) AF: 0.00718 AC: 171 AN: 23830

American (AMR) AF: 0.0248 AC: 936 AN: 37704

Ashkenazi Jewish (ASJ) AF: 0.0128 AC: 291 AN: 22766

East Asian (EAS) AF: 0.0377 AC: 1310 AN: 34744

South Asian (SAS) AF: 0.0344 AC: 2510 AN: 72998

European-Finnish (FIN) AF: 0.0641 AC: 2946 AN: 45984

Middle Eastern (MID) AF: 0.0181 AC: 76 AN: 4198

European-Non Finnish (NFE) AF: 0.0547 AC: 38620 AN: 706206

Other (OTH) AF: 0.0478 AC: 2151 AN: 45028

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

African (AFR) AF: 0.00886 AC: 368 AN: 41552

American (AMR) AF: 0.0290 AC: 444 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3468

East Asian (EAS) AF: 0.0299 AC: 155 AN: 5188

South Asian (SAS) AF: 0.0335 AC: 162 AN: 4830

European-Finnish (FIN) AF: 0.0708 AC: 750 AN: 10600

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0561 AC: 3818 AN: 68002

Other (OTH) AF: 0.0379 AC: 80 AN: 2110

Alfa AF: 0.0362 Hom.: 68

Bravo AF: 0.0339

Asia WGS AF: 0.0420 AC: 146 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 10, 2018

GeneDx

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.3
DANN	Benign	0.61
PhyloP100		-0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=98/2	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: rs2306196; hg19: chr19-39205015; COSMIC: COSV53147653; COSMIC: COSV53147653;