19-9653604-C-G

Variant names:

• chr19-9653604-C-G
• rs771425297
• NM_001130031.2:c.626G>C

Variant summary

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

The NM_001130031.2(ZNF562):​c.626G>C​(p.Cys209Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,802 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: 0.0000027 (0 hom.)
• Consequence: ZNF562 NM_001130031.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.790

Genes affected

ZNF562 (HGNC:25950): (zinc finger protein 562) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription, DNA-templated. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF561-AS1 (HGNC:27613): (ZNF561 antisense RNA 1 (head to head))

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
ZNF562	NM_001130031.2	c.626G>C	p.Cys209Ser	missense_variant	Exon 6 of 6	ENST00000453372.7	NP_001123503.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF562	ENST00000453372.7	c.626G>C	p.Cys209Ser	missense_variant	Exon 6 of 6	3	NM_001130031.2	ENSP00000410734.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461802 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.626G>C (p.C209S) alteration is located in exon 6 (coding exon 5) of the ZNF562 gene. This alteration results from a G to C substitution at nucleotide position 626, causing the cysteine (C) at amino acid position 209 to be replaced by a serine (S). 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	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	12
DANN	Benign	0.81
DEOGEN2	Benign	0.13	.;T;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.0095	T
MetaRNN	Uncertain	0.65	D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	4.0	.;H;.
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-8.0	D;D;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.027	D;D;.
Sift4G	Uncertain	0.015	D;T;T
Polyphen		0.0010	B;B;.
Vest4		0.27
MutPred		0.73		.;Gain of disorder (P = 0.0021);.;
MVP		0.93
ClinPred		0.22	T
GERP RS		0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.40
gMVP		0.22

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: rs771425297; hg19: chr19-9764280;