rs2287728

Variant names:

• chr19-38704918-C-T
• rs2287728
• NM_004924.6:c.398-16C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-38704918-C-T
• chr19-38704918-C-G

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.398-16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0644 in 1,611,324 control chromosomes in the GnomAD database, including 3,696 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (251 hom., cov: 33)
  • Exomes 𝑓: 0.065 (3445 hom.)
• Consequence: ACTN4 NM_004924.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.466
• Publications: 10 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

ENSG00000298338 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-38704918-C-T is Benign according to our data. Variant chr19-38704918-C-T is described in ClinVar as Benign. ClinVar VariationId is 259579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0888 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.398-16C>T		intron	N/A	NP_004915.2
	ACTN4	NM_001440296.1		c.398-16C>T		intron	N/A	NP_001427225.1
	ACTN4	NM_001440300.1		c.398-16C>T		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.398-16C>T		intron	N/A	ENSP00000252699.2	O43707-1
	ACTN4	ENST00000424234.7	TSL:1	c.398-16C>T		intron	N/A	ENSP00000411187.4	F5GXS2
	ACTN4	ENST00000390009.7	TSL:1	c.163-9551C>T		intron	N/A	ENSP00000439497.1	O43707-2

Frequencies

GnomAD3 genomes AF: 0.0558 AC: 8485 AN: 152186 Hom.: 252 Cov.: 33

Gnomad AFR AF: 0.0484

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0578

Gnomad ASJ AF: 0.0565

Gnomad EAS AF: 0.0460

Gnomad SAS AF: 0.0965

Gnomad FIN AF: 0.0219

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0633

Gnomad OTH AF: 0.0583

GnomAD2 exomes AF: 0.0623 AC: 15652 AN: 251436 AF XY: 0.0639

Gnomad AFR exome AF: 0.0493

Gnomad AMR exome AF: 0.0678

Gnomad ASJ exome AF: 0.0604

Gnomad EAS exome AF: 0.0397

Gnomad FIN exome AF: 0.0231

Gnomad NFE exome AF: 0.0621

Gnomad OTH exome AF: 0.0662

GnomAD4 exome AF: 0.0653 AC: 95220 AN: 1459020 Hom.: 3445 Cov.: 31 AF XY: 0.0662 AC XY: 48087 AN XY: 726130

African (AFR) AF: 0.0499 AC: 1667 AN: 33424

American (AMR) AF: 0.0709 AC: 3170 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0622 AC: 1624 AN: 26126

East Asian (EAS) AF: 0.0453 AC: 1799 AN: 39690

South Asian (SAS) AF: 0.102 AC: 8750 AN: 86198

European-Finnish (FIN) AF: 0.0251 AC: 1338 AN: 53410

Middle Eastern (MID) AF: 0.0686 AC: 395 AN: 5760

European-Non Finnish (NFE) AF: 0.0654 AC: 72548 AN: 1109396

Other (OTH) AF: 0.0652 AC: 3929 AN: 60300

GnomAD4 genome AF: 0.0557 AC: 8489 AN: 152304 Hom.: 251 Cov.: 33 AF XY: 0.0548 AC XY: 4084 AN XY: 74470

African (AFR) AF: 0.0484 AC: 2013 AN: 41550

American (AMR) AF: 0.0577 AC: 883 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0565 AC: 196 AN: 3472

East Asian (EAS) AF: 0.0461 AC: 239 AN: 5184

South Asian (SAS) AF: 0.0960 AC: 463 AN: 4824

European-Finnish (FIN) AF: 0.0219 AC: 233 AN: 10620

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0633 AC: 4309 AN: 68022

Other (OTH) AF: 0.0591 AC: 125 AN: 2116

Alfa AF: 0.0631 Hom.: 392

Bravo AF: 0.0584

Asia WGS AF: 0.0890 AC: 308 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Focal segmental glomerulosclerosis 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.9
DANN	Benign	0.74
PhyloP100		-0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
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: rs2287728; hg19: chr19-39195558; COSMIC: COSV53148868; COSMIC: COSV53148868;