15-84782866-C-T

Variant names:

• chr15-84782866-C-T
• rs1387827683
• NM_014630.3:c.191C>T

Variant summary

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

The NM_014630.3(ZNF592):​c.191C>T​(p.Pro64Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ZNF592 NM_014630.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.46

Genes affected

ZNF592 (HGNC:28986): (zinc finger protein 592) This gene is thought to play a role in a complex developmental pathway and the regulation of genes involved in cerebellar development. Mutations in this gene have been associated with autosomal recessive spinocerebellar ataxia. [provided by RefSeq, Jan 2011]

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 rank	MANE	Protein	UniProt
ZNF592	NM_014630.3	c.191C>T	p.Pro64Leu	missense_variant	Exon 4 of 11	ENST00000560079.7	NP_055445.2
ZNF592	XM_005254996.4	c.191C>T	p.Pro64Leu	missense_variant	Exon 3 of 10		XP_005255053.1
ZNF592	XM_011522246.3	c.191C>T	p.Pro64Leu	missense_variant	Exon 4 of 11		XP_011520548.1
ZNF592	XM_011522247.3	c.191C>T	p.Pro64Leu	missense_variant	Exon 3 of 10		XP_011520549.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF592	ENST00000560079.7	c.191C>T	p.Pro64Leu	missense_variant	Exon 4 of 11	1	NM_014630.3	ENSP00000452877.2
ZNF592	ENST00000559607.1	n.191C>T		non_coding_transcript_exon_variant	Exon 2 of 9	1		ENSP00000453491.1
ZNF592	ENST00000299927.4	c.191C>T	p.Pro64Leu	missense_variant	Exon 1 of 8	2		ENSP00000299927.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.191C>T (p.P64L) alteration is located in exon 4 (coding exon 1) of the ZNF592 gene. This alteration results from a C to T substitution at nucleotide position 191, causing the proline (P) at amino acid position 64 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.26	T;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;D
Vest4		0.63
MutPred		0.31		Gain of sheet (P = 0.0061);Gain of sheet (P = 0.0061);
MVP		0.20
MPC		0.94
ClinPred		0.99	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.42

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: rs1387827683; hg19: chr15-85326097;