rs759248853

Variant names:

• chr20-33667709-C-A
• rs759248853
• NM_001024675.2:c.212C>A

Your query was ambiguous. Multiple possible variants found:

• chr20-33667709-C-A
• chr20-33667709-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001024675.2(ACTL10):​c.212C>A​(p.Ala71Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,740 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A71V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ACTL10 NM_001024675.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.01
• Publications: 0 publications found

Genes affected

ACTL10 (HGNC:16127): (actin like 10) Predicted to be part of dynactin complex. [provided by Alliance of Genome Resources, Apr 2022]

NECAB3 (HGNC:15851): (N-terminal EF-hand calcium binding protein 3) The protein encoded by this gene interacts with the amino-terminal domain of the neuron-specific X11-like protein (X11L), inhibits the association of X11L with amyloid precursor protein through a non-competitive mechanism, and abolishes the suppression of beta-amyloid production by X11L. This protein, together with X11L, may play an important role in the regulatory system of amyloid precursor protein metabolism and beta-amyloid generation. The protein is phosphorylated by NIMA-related expressed kinase 2, and localizes to the Golgi apparatus. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001024675.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTL10	NM_001024675.2	MANE Select	c.212C>A	p.Ala71Asp	missense	Exon 1 of 1	NP_001019846.1	Q5JWF8
	NECAB3	NM_031232.4	MANE Select	c.387+1666G>T		intron	N/A	NP_112509.3
	NECAB3	NM_031231.4		c.387+1666G>T		intron	N/A	NP_112508.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTL10	ENST00000677665.1	MANE Select	c.212C>A	p.Ala71Asp	missense	Exon 1 of 1	ENSP00000504425.1	Q5JWF8
	NECAB3	ENST00000246190.11	TSL:5 MANE Select	c.387+1666G>T		intron	N/A	ENSP00000246190.6	Q96P71-1
	NECAB3	ENST00000375238.8	TSL:1	c.387+1666G>T		intron	N/A	ENSP00000364386.4	Q96P71-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000406 AC: 1 AN: 246018 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459740 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726240

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51466

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111878

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	1.8	L
PhyloP100		1.0
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.012	D
Polyphen		0.78	P
Vest4		0.17
MutPred		0.70		Gain of solvent accessibility (P = 0.0648)
MVP		0.35
MPC		0.95
ClinPred		0.93	D
GERP RS		0.39
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.9
Varity_R		0.66
gMVP		0.54
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs759248853; hg19: chr20-32255515;