dbSNP rs387907346: ACTN1:p.Gln32Lys (chr14-68978963-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP5

The NM_001130004.2(ACTN1):c.94C>A(p.Gln32Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q32R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ACTN1
NM_001130004.2 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.60

Publications

5 publications found

Variant links:

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 links:

ACTN1-DT (HGNC:20131): (ACTN1 divergent transcript)

ACTN1-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 14-68978963-G-T is Pathogenic according to our data. Variant chr14-68978963-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 42029.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACTN1	NM_001130004.2	MANE Select	c.94C>A	p.Gln32Lys	missense	Exon 1 of 22	NP_001123476.1	P12814-3
ACTN1	NM_001424012.1		c.94C>A	p.Gln32Lys	missense	Exon 1 of 21	NP_001410941.1
ACTN1	NM_001424013.1		c.94C>A	p.Gln32Lys	missense	Exon 1 of 22	NP_001410942.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACTN1	ENST00000394419.9	TSL:1 MANE Select	c.94C>A	p.Gln32Lys	missense	Exon 1 of 22	ENSP00000377941.4	P12814-3
ACTN1	ENST00000538545.6	TSL:1	c.94C>A	p.Gln32Lys	missense	Exon 1 of 21	ENSP00000439828.2	P12814-4
ACTN1	ENST00000193403.11	TSL:1	c.94C>A	p.Gln32Lys	missense	Exon 1 of 21	ENSP00000193403.6	P12814-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1445042

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719134

African (AFR)

AF:

0.00

AC:

AN:

32368

American (AMR)

AF:

0.00

AC:

AN:

42952

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25716

East Asian (EAS)

AF:

0.00

AC:

AN:

38448

South Asian (SAS)

AF:

0.00

AC:

AN:

84290

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53118

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5480

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102962

Other (OTH)

AF:

0.00

AC:

AN:

59708

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Platelet-type bleeding disorder 15 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.79

M_CAP

Pathogenic

0.84

MetaRNN

Uncertain

0.69

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

1.8

PhyloP100

5.6

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.2

REVEL

Uncertain

0.44

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.059

Polyphen

0.73

Vest4

0.51

MutPred

0.54

Gain of catalytic residue at Q33 (P = 0.0135)

MVP

0.87

MPC

1.8

ClinPred

0.98

GERP RS

5.0

PromoterAI

0.030

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

3.8

Varity_R

0.94

gMVP

0.85

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over