20-33667709-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001024675.2(ACTL10):​c.212C>T​(p.Ala71Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,611,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ACTL10 NM_001024675.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2853882).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

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>T	p.Ala71Val	missense	Exon 1 of 1	NP_001019846.1	Q5JWF8
	NECAB3	NM_031232.4	MANE Select	c.387+1666G>A		intron	N/A	NP_112509.3
	NECAB3	NM_031231.4		c.387+1666G>A		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>T	p.Ala71Val	missense	Exon 1 of 1	ENSP00000504425.1	Q5JWF8
	NECAB3	ENST00000246190.11	TSL:5 MANE Select	c.387+1666G>A		intron	N/A	ENSP00000246190.6	Q96P71-1
	NECAB3	ENST00000375238.8	TSL:1	c.387+1666G>A		intron	N/A	ENSP00000364386.4	Q96P71-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 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: 0.00000343 AC: 5 AN: 1459740 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 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: 0.00 AC: 0 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: 0.00000360 AC: 4 AN: 1111878

Other (OTH) AF: 0.0000166 AC: 1 AN: 60366

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152224 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74360

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	1.9	L
PhyloP100		1.0
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.018	D
Polyphen		0.084	B
Vest4		0.074
MutPred		0.65		Gain of methylation at K75 (P = 0.0768)
MVP		0.32
MPC		0.55
ClinPred		0.83	D
GERP RS		0.39
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.9
Varity_R		0.47
gMVP		0.41
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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; COSMIC: COSV99864776; COSMIC: COSV99864776;