14-68874941-G-A

Position:

chr14-68874941-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001130004.2(ACTN1):c.2663C>T(p.Pro888Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,613,318 control chromosomes in the GnomAD database, including 525 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 39 hom., cov: 33)

Exomes 𝑓: 0.024 ( 486 hom. )

Consequence

ACTN1
NM_001130004.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 10.0

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 (HGNC:):

ACTN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACTN1. . Gene score misZ 3.3621 (greater than the threshold 3.09). Trascript score misZ 5.1933 (greater than threshold 3.09). GenCC has associacion of gene with autosomal dominant macrothrombocytopenia, platelet-type bleeding disorder 15.

BP4

Computational evidence support a benign effect (MetaRNN=0.007120222).

BP6

Variant 14-68874941-G-A is Benign according to our data. Variant chr14-68874941-G-A is described in ClinVar as [Benign]. Clinvar id is 1205893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-68874941-G-A is described in Lovd as [Benign]. Variant chr14-68874941-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0179 (2729/152322) while in subpopulation NFE AF= 0.0258 (1757/68020). AF 95% confidence interval is 0.0248. There are 39 homozygotes in gnomad4. There are 1320 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2729 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTN1	NM_001130004.2 linkuse as main transcript	c.2663C>T	p.Pro888Leu	missense_variant	22/22	ENST00000394419.9	NP_001123476.1	P12814-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTN1	ENST00000394419.9 linkuse as main transcript	c.2663C>T	p.Pro888Leu	missense_variant	22/22	1	NM_001130004.2	ENSP00000377941.4		P12814-3

Frequencies

GnomAD3 genomes

AF:

0.0179

AC:

2729

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00425

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0122

Gnomad ASJ

AF:

0.0472

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0103

Gnomad FIN

AF:

0.0326

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0258

Gnomad OTH

AF:

0.0220

GnomAD3 exomes

AF:

0.0204

AC:

5094

AN:

250002

Hom.:

AF XY:

0.0210

AC XY:

2845

AN XY:

135414

show subpopulations

Gnomad AFR exome

AF:

0.00385

Gnomad AMR exome

AF:

0.0107

Gnomad ASJ exome

AF:

0.0526

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0103

Gnomad FIN exome

AF:

0.0358

Gnomad NFE exome

AF:

0.0259

Gnomad OTH exome

AF:

0.0208

GnomAD4 exome

AF:

0.0236

AC:

34463

AN:

1460996

Hom.:

486

Cov.:

AF XY:

0.0234

AC XY:

17039

AN XY:

726718

show subpopulations

Gnomad4 AFR exome

AF:

0.00323

Gnomad4 AMR exome

AF:

0.0113

Gnomad4 ASJ exome

AF:

0.0518

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0108

Gnomad4 FIN exome

AF:

0.0349

Gnomad4 NFE exome

AF:

0.0254

Gnomad4 OTH exome

AF:

0.0222

GnomAD4 genome

AF:

0.0179

AC:

2729

AN:

152322

Hom.:

Cov.:

AF XY:

0.0177

AC XY:

1320

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00423

Gnomad4 AMR

AF:

0.0122

Gnomad4 ASJ

AF:

0.0472

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.0103

Gnomad4 FIN

AF:

0.0326

Gnomad4 NFE

AF:

0.0258

Gnomad4 OTH

AF:

0.0217

Alfa

AF:

0.0241

Hom.:

Bravo

AF:

0.0163

TwinsUK

AF:

0.0251

AC:

ALSPAC

AF:

0.0288

AC:

111

ESP6500AA

AF:

0.00545

AC:

ESP6500EA

AF:

0.0264

AC:

227

ExAC

AF:

0.0197

AC:

2393

Asia WGS

AF:

0.00751

AC:

AN:

3478

EpiCase

AF:

0.0262

EpiControl

AF:

0.0247

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.26

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

T;.;.;T;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

D;D;D;D;D

MetaRNN

Benign

0.0071

T;T;T;T;T

MetaSVM

Benign

-0.69

MutationAssessor

Uncertain

2.2

M;.;.;.;.

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.4

D;D;D;D;D

REVEL

Uncertain

0.33

Sift

Uncertain

0.0050

D;D;D;D;D

Sift4G

Uncertain

0.032

D;D;D;D;D

Polyphen

0.30

B;.;P;.;.

Vest4

0.71

MPC

0.14

ClinPred

0.041

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.47

gMVP

0.65

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over