14-68874941-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

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
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 10.0

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 Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ACTN1
• 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_single_submitter, 1 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 GnomAd at 2729 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN1	NM_001130004.2	c.2663C>T	p.Pro888Leu	missense_variant	22/22	ENST00000394419.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN1	ENST00000394419.9	c.2663C>T	p.Pro888Leu	missense_variant	22/22	1	NM_001130004.2	P3

Frequencies

GnomAD3 genomes AF: 0.0179 AC: 2729 AN: 152204 Hom.: 39 Cov.: 33

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.: 58 AF XY: 0.0210 AC XY: 2845 AN XY: 135414

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.: 31 AF XY: 0.0234 AC XY: 17039 AN XY: 726718

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.: 39 Cov.: 33 AF XY: 0.0177 AC XY: 1320 AN XY: 74472

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.: 38

Bravo AF: 0.0163

TwinsUK AF: 0.0251 AC: 93

ALSPAC AF: 0.0288 AC: 111

ESP6500AA AF: 0.00545 AC: 24

ESP6500EA AF: 0.0264 AC: 227

ExAC AF: 0.0197 AC: 2393

Asia WGS AF: 0.00751 AC: 27 AN: 3478

EpiCase AF: 0.0262

EpiControl AF: 0.0247

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.26
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.;.;T;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
MetaRNN	Benign	0.0071	T;T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.2	M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.78	T
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	T
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

Other links and lift over

dbSNP: rs77499007; hg19: chr14-69341658; COSMIC: COSV99060997; COSMIC: COSV99060997;