rs2112649

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr19-38700743-G-C
• chr19-38700743-G-A
• chr19-38700743-G-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.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
• Publications: 11 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN4	NM_004924.6	MANE Select	c.277+29G>C		intron	N/A	NP_004915.2
	ACTN4	NM_001440296.1		c.277+29G>C		intron	N/A	NP_001427225.1
	ACTN4	NM_001440300.1		c.277+29G>C		intron	N/A	NP_001427229.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN4	ENST00000252699.7	TSL:1 MANE Select	c.277+29G>C		intron	N/A	ENSP00000252699.2	O43707-1
	ACTN4	ENST00000424234.7	TSL:1	c.277+29G>C		intron	N/A	ENSP00000411187.4	F5GXS2
	ACTN4	ENST00000390009.7	TSL:1	c.163-13726G>C		intron	N/A	ENSP00000439497.1	O43707-2

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

GnomAD2 exomes AF: 0.719 AC: 177912 AN: 247446 AF XY: 0.733

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 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

African (AFR) AF: 0.540 AC: 17764 AN: 32886

American (AMR) AF: 0.606 AC: 26921 AN: 44434

Ashkenazi Jewish (ASJ) AF: 0.709 AC: 18408 AN: 25974

East Asian (EAS) AF: 0.685 AC: 27051 AN: 39514

South Asian (SAS) AF: 0.851 AC: 72920 AN: 85696

European-Finnish (FIN) AF: 0.728 AC: 37925 AN: 52104

Middle Eastern (MID) AF: 0.740 AC: 4136 AN: 5590

European-Non Finnish (NFE) AF: 0.756 AC: 824449 AN: 1090038

Other (OTH) AF: 0.736 AC: 43830 AN: 59588

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

African (AFR) AF: 0.544 AC: 22551 AN: 41454

American (AMR) AF: 0.653 AC: 9987 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.713 AC: 2474 AN: 3470

East Asian (EAS) AF: 0.628 AC: 3244 AN: 5162

South Asian (SAS) AF: 0.844 AC: 4069 AN: 4822

European-Finnish (FIN) AF: 0.728 AC: 7698 AN: 10568

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.754 AC: 51272 AN: 67990

Other (OTH) AF: 0.698 AC: 1473 AN: 2110

Alfa AF: 0.689 Hom.: 4419

Bravo AF: 0.666

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Focal segmental glomerulosclerosis 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.8
DANN	Benign	0.65
PhyloP100		0.0020
RBP_binding_hub_radar		0.85
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	polymorphism (auto)

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