chr2-97658451-A-T

Position:

• chr2-97658451-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005735.4(ACTR1B):​c.633T>A​(p.Phe211Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACTR1B NM_005735.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.25

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTR1B	NM_005735.4	c.633T>A	p.Phe211Leu	missense_variant	6/11	ENST00000289228.7	NP_005726.1
ACTR1B	XM_017003116.2	c.501T>A	p.Phe167Leu	missense_variant	6/11		XP_016858605.1
ACTR1B	XM_005263854.6	c.411T>A	p.Phe137Leu	missense_variant	5/10		XP_005263911.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTR1B	ENST00000289228.7	c.633T>A	p.Phe211Leu	missense_variant	6/11	1	NM_005735.4	ENSP00000289228	P1
ACTR1B	ENST00000451664.1	n.894T>A		non_coding_transcript_exon_variant	5/7	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Duane retraction syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Feb 27, 2024

The heterozygous p.Phe211Leu variant in ACTR1B was identified in 1 individual with Duane retraction syndrome (DRS) with congenital ptosis via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/. While this gene is still lacking sufficient evidence to establish a gene-disease association, we believe this is a possible novel gene candidate for DRS. Given the limited information about this gene-disease relationship, the significance of the p.Phe211Leu variant is uncertain. If you have any additional information about functional evidence or other individuals with this phenotype that also have variants in ACTR1B we encourage you to reach out to the Engle Lab (elizabeth.engle@childrens.harvard.edu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	16
DANN	Benign	0.82
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.0	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.36
Sift	Benign	1.0	T
Sift4G	Benign	0.35	T
Polyphen		0.0010	B
Vest4		0.78
MutPred		0.52		Loss of helix (P = 0.1299);
MVP		0.77
MPC		0.47
ClinPred		0.23	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.61

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: rs1674916713; hg19: chr2-98274914;