19-3905459-C-T

Variant names:

• chr19-3905459-C-T
• rs373392142
• NM_033064.5:c.162C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_033064.5(ATCAY):​c.162C>T​(p.Asn54Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,612,008 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (4 hom.)
• Consequence: ATCAY NM_033064.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -2.81
• Publications: 2 publications found

Genes affected

ATCAY (HGNC:779): (ATCAY kinesin light chain interacting caytaxin) This gene encodes a neuron-restricted protein that contains a CRAL-TRIO motif common to proteins that bind small lipophilic molecules. Mutations in this gene are associated with cerebellar ataxia, Cayman type. [provided by RefSeq, Jul 2008]

ATCAY Gene-Disease associations (from GenCC):

• cerebellar ataxia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Cayman type cerebellar ataxia

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 19-3905459-C-T is Benign according to our data. Variant chr19-3905459-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 329118.
• BP7: Synonymous conserved (PhyloP=-2.81 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033064.5. 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
	ATCAY	NM_033064.5	MANE Select	c.162C>T	p.Asn54Asn	synonymous	Exon 4 of 13	NP_149053.1	A0A0S2Z5T8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATCAY	ENST00000450849.7	TSL:1 MANE Select	c.162C>T	p.Asn54Asn	synonymous	Exon 4 of 13	ENSP00000390941.1	Q86WG3-1
	ATCAY	ENST00000861418.1		c.162C>T	p.Asn54Asn	synonymous	Exon 4 of 13	ENSP00000531477.1
	ATCAY	ENST00000600960.1	TSL:5	c.162C>T	p.Asn54Asn	synonymous	Exon 3 of 13	ENSP00000470842.1	Q86WG3-3

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000167 AC: 41 AN: 245242 AF XY: 0.000218

Gnomad AFR exome AF: 0.000262

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.000394

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000190

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000142 AC: 207 AN: 1459726 Hom.: 4 Cov.: 31 AF XY: 0.000150 AC XY: 109 AN XY: 725962

African (AFR) AF: 0.0000598 AC: 2 AN: 33428

American (AMR) AF: 0.0000678 AC: 3 AN: 44264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26028

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39672

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00659 AC: 38 AN: 5768

European-Non Finnish (NFE) AF: 0.000105 AC: 117 AN: 1110852

Other (OTH) AF: 0.000298 AC: 18 AN: 60330

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74454

African (AFR) AF: 0.000216 AC: 9 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15270

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

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.000196

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Cayman type cerebellar ataxia (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.20
DANN	Benign	0.45
PhyloP100		-2.8
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs373392142; hg19: chr19-3905457; COSMIC: COSV56654547;