14-68874992-C-A

Variant names:

• chr14-68874992-C-A
• rs371440985
• NM_001130004.2:c.2612G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001130004.2(ACTN1):​c.2612G>T​(p.Arg871Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACTN1 NM_001130004.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.11

Genes affected

ACTN1 (HGNC:163): (actinin alpha 1) 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, cytoskeletal, alpha actinin isoform and maps to the same site as the structurally similar erythroid beta spectrin gene. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the ACTN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 22 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 3.3621 (above the threshold of 3.09). Trascript score misZ: 5.1933 (above the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant macrothrombocytopenia, platelet-type bleeding disorder 15.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN1	NM_001130004.2	c.2612G>T	p.Arg871Leu	missense_variant	Exon 22 of 22	ENST00000394419.9	NP_001123476.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN1	ENST00000394419.9	c.2612G>T	p.Arg871Leu	missense_variant	Exon 22 of 22	1	NM_001130004.2	ENSP00000377941.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;.;.;T;.
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.56	D;D;D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.2	M;.;.;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.4	D;D;D;D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0050	D;D;D;D;D
Sift4G	Uncertain	0.015	D;D;D;D;D
Polyphen		0.016	B;.;B;.;.
Vest4		0.54
MutPred		0.75		Gain of catalytic residue at P853 (P = 0.001);.;.;.;.;
MVP		0.48
MPC		0.052
ClinPred		0.98	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.65
gMVP		0.77

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: rs371440985; hg19: chr14-69341709;