NM_004924.6:c.277+29G>C

Variant names:

• chr19-38700743-G-C
• rs2112649
• NM_004924.6:c.277+29G>C

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.277+29G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.741 in 1,587,894 control chromosomes in the GnomAD database, including 439,591 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (36213 hom., cov: 32)
  • Exomes 𝑓: 0.75 (403378 hom.)
• Consequence: ACTN4 NM_004924.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.00200

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-38700743-G-C is Benign according to our data. Variant chr19-38700743-G-C is described in ClinVar as [Benign]. Clinvar id is 1259827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.822 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN4	NM_004924.6	c.277+29G>C		intron_variant	Intron 2 of 20	ENST00000252699.7	NP_004915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN4	ENST00000252699.7	c.277+29G>C		intron_variant	Intron 2 of 20	1	NM_004924.6	ENSP00000252699.2

Frequencies

GnomAD3 genomes AF: 0.683 AC: 103710 AN: 151952 Hom.: 36189 Cov.: 32

Gnomad AFR AF: 0.544

Gnomad AMI AF: 0.884

Gnomad AMR AF: 0.654

Gnomad ASJ AF: 0.713

Gnomad EAS AF: 0.628

Gnomad SAS AF: 0.845

Gnomad FIN AF: 0.728

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.754

Gnomad OTH AF: 0.695

GnomAD3 exomes AF: 0.719 AC: 177912 AN: 247446 Hom.: 64847 AF XY: 0.733 AC XY: 98264 AN XY: 134004

Gnomad AFR exome AF: 0.544

Gnomad AMR exome AF: 0.607

Gnomad ASJ exome AF: 0.712

Gnomad EAS exome AF: 0.611

Gnomad SAS exome AF: 0.854

Gnomad FIN exome AF: 0.729

Gnomad NFE exome AF: 0.757

Gnomad OTH exome AF: 0.731

GnomAD4 exome AF: 0.748 AC: 1073404 AN: 1435824 Hom.: 403378 Cov.: 28 AF XY: 0.751 AC XY: 537705 AN XY: 715702

Gnomad4 AFR exome AF: 0.540

Gnomad4 AMR exome AF: 0.606

Gnomad4 ASJ exome AF: 0.709

Gnomad4 EAS exome AF: 0.685

Gnomad4 SAS exome AF: 0.851

Gnomad4 FIN exome AF: 0.728

Gnomad4 NFE exome AF: 0.756

Gnomad4 OTH exome AF: 0.736

GnomAD4 genome AF: 0.682 AC: 103777 AN: 152070 Hom.: 36213 Cov.: 32 AF XY: 0.683 AC XY: 50761 AN XY: 74328

Gnomad4 AFR AF: 0.544

Gnomad4 AMR AF: 0.653

Gnomad4 ASJ AF: 0.713

Gnomad4 EAS AF: 0.628

Gnomad4 SAS AF: 0.844

Gnomad4 FIN AF: 0.728

Gnomad4 NFE AF: 0.754

Gnomad4 OTH AF: 0.698

Alfa AF: 0.689 Hom.: 4419

Bravo AF: 0.666

ClinVar

Significance: Benign

Submissions summary: Benign:4

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 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 82% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 76. Only high quality variants are reported. -

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	-0.89
CADD	Benign	3.8
DANN	Benign	0.65
RBP_binding_hub_radar		0.85
RBP_regulation_power_radar		2.1

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: rs2112649; hg19: chr19-39191383; COSMIC: COSV53143737;