chr2-97658891-G-A

Position:

• chr2-97658891-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3 BA1

The ENST00000289228.7(ACTR1B):​c.428C>T​(p.Ala143Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0773 in 1,613,986 control chromosomes in the GnomAD database, including 6,471 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.065 (646 hom., cov: 32)
  • Exomes 𝑓: 0.079 (5825 hom.)
• Consequence: ACTR1B ENST00000289228.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.86

Genes affected

ACTR1B (HGNC:168): (actin related protein 1B) This gene encodes a 42.3 kD subunit of dynactin, a macromolecular complex consisting of 10 subunits ranging in size from 22 to 150 kD. Dynactin binds to both microtubules and cytoplasmic dynein and is involved in a diverse array of cellular functions, including ER-to-Golgi transport, the centripetal movement of lysosomes and endosomes, spindle formation, chromosome movement, nuclear positioning, and axonogenesis. This subunit, like ACTR1A, is an actin-related protein. These two proteins, which are of equal length and share 90% amino acid identity, are present in a constant ratio of approximately 1:15 in the dynactin complex. [provided by RefSeq, Aug 2008]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_noAF, Cadd, Dann, max_spliceai, Eigen, MutationAssessor, phyloP100way_vertebrate, PrimateAI, REVEL [when BayesDel_addAF, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0833 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTR1B	NM_005735.4	c.428C>T	p.Ala143Val	missense_variant	5/11	ENST00000289228.7	NP_005726.1
ACTR1B	XM_017003116.2	c.296C>T	p.Ala99Val	missense_variant	5/11		XP_016858605.1
ACTR1B	XM_005263854.6	c.206C>T	p.Ala69Val	missense_variant	4/10		XP_005263911.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTR1B	ENST00000289228.7	c.428C>T	p.Ala143Val	missense_variant	5/11	1	NM_005735.4	ENSP00000289228	P1
ACTR1B	ENST00000451664.1	n.454C>T		non_coding_transcript_exon_variant	5/7	5
ACTR1B	ENST00000460427.2	n.653C>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.0649 AC: 9874 AN: 152032 Hom.: 646 Cov.: 32

Gnomad AFR AF: 0.0119

Gnomad AMI AF: 0.0813

Gnomad AMR AF: 0.0409

Gnomad ASJ AF: 0.0357

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0851

Gnomad OTH AF: 0.0511

GnomAD3 exomes AF: 0.0700 AC: 17602 AN: 251390 Hom.: 1254 AF XY: 0.0696 AC XY: 9456 AN XY: 135868

Gnomad AFR exome AF: 0.0115

Gnomad AMR exome AF: 0.0249

Gnomad ASJ exome AF: 0.0390

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0145

Gnomad FIN exome AF: 0.243

Gnomad NFE exome AF: 0.0887

Gnomad OTH exome AF: 0.0624

GnomAD4 exome AF: 0.0786 AC: 114874 AN: 1461836 Hom.: 5825 Cov.: 33 AF XY: 0.0768 AC XY: 55886 AN XY: 727224

Gnomad4 AFR exome AF: 0.0107

Gnomad4 AMR exome AF: 0.0257

Gnomad4 ASJ exome AF: 0.0389

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0165

Gnomad4 FIN exome AF: 0.234

Gnomad4 NFE exome AF: 0.0851

Gnomad4 OTH exome AF: 0.0620

GnomAD4 genome AF: 0.0649 AC: 9875 AN: 152150 Hom.: 646 Cov.: 32 AF XY: 0.0708 AC XY: 5263 AN XY: 74352

Gnomad4 AFR AF: 0.0119

Gnomad4 AMR AF: 0.0409

Gnomad4 ASJ AF: 0.0357

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0141

Gnomad4 FIN AF: 0.246

Gnomad4 NFE AF: 0.0851

Gnomad4 OTH AF: 0.0506

Alfa AF: 0.0737 Hom.: 1252

Bravo AF: 0.0485

TwinsUK AF: 0.0831 AC: 308

ALSPAC AF: 0.0825 AC: 318

ESP6500AA AF: 0.0159 AC: 70

ESP6500EA AF: 0.0833 AC: 716

ExAC AF: 0.0689 AC: 8371

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Benign	0.0033	T
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Pathogenic	4.1	H
MutationTaster	Benign	1.9e-9	P
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.36
MPC		1.2
ClinPred		0.089	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.76		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs11692435; hg19: chr2-98275354; COSMIC: COSV56705212;