14-68880030-G-C

Variant names:

• chr14-68880030-G-C
• rs387907349
• NM_001130004.2:c.2212C>G
• ACTN1 p.Arg738Gly

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3 PP5

The NM_001130004.2(ACTN1):​c.2212C>G​(p.Arg738Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R738Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTN1 NM_001130004.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 3.41
• Publications: 11 publications found

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]

ACTN1 Gene-Disease associations (from GenCC):

• platelet-type bleeding disorder 15

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant macrothrombocytopenia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001130004.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-68880029-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1684471.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839
• PP5: Variant 14-68880030-G-C is Pathogenic according to our data. Variant chr14-68880030-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 872047.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130004.2. 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
	ACTN1	NM_001130004.2	MANE Select	c.2212C>G	p.Arg738Gly	missense	Exon 18 of 22	NP_001123476.1	P12814-3
	ACTN1	NM_001424012.1		c.2212C>G	p.Arg738Gly	missense	Exon 18 of 21	NP_001410941.1
	ACTN1	NM_001424013.1		c.2338C>G	p.Arg780Gly	missense	Exon 19 of 22	NP_001410942.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN1	ENST00000394419.9	TSL:1 MANE Select	c.2212C>G	p.Arg738Gly	missense	Exon 18 of 22	ENSP00000377941.4	P12814-3
	ACTN1	ENST00000538545.6	TSL:1	c.2212C>G	p.Arg738Gly	missense	Exon 18 of 21	ENSP00000439828.2	P12814-4
	ACTN1	ENST00000193403.11	TSL:1	c.2212C>G	p.Arg738Gly	missense	Exon 18 of 21	ENSP00000193403.6	P12814-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		3.4
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.95
Mutation Taster		=20/80	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs387907349;

hg19: chr14-69346747;