19-57978518-G-A

Position:

• chr19-57978518-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001348022.3(ZNF606):​c.2162C>T​(p.Ser721Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF606 NM_001348022.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.21

Genes affected

ZNF606 (HGNC:25879): (zinc finger protein 606) This gene encodes a zinc finger protein containing a Kruppel-associated box (KRAB) domain at its N-terminus, followed by contiguous C2H2 zinc finger motifs. The encoded protein is a nuclear protein that can act as a transcriptional repressor of growth factor-mediated signaling pathways in a reporter gene assay. This protein has been shown to interact with the SRY-box 9 gene product, and suppresses its transcriptional activity by inhibiting its DNA binding activity. Reduced expression of this gene promotes chondrocyte differentiation. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17456102).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF606	NM_001348022.3	c.2162C>T	p.Ser721Leu	missense_variant	7/7	ENST00000551380.7	NP_001334951.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF606	ENST00000551380.7	c.2162C>T	p.Ser721Leu	missense_variant	7/7	5	NM_001348022.3	ENSP00000446972.2
ZNF606	ENST00000341164.9	c.2162C>T	p.Ser721Leu	missense_variant	7/7	1		ENSP00000343617.4
ZNF606	ENST00000550599.6	n.*1896C>T		non_coding_transcript_exon_variant	6/6	2		ENSP00000446845.1
ZNF606	ENST00000550599.6	n.*1896C>T		3_prime_UTR_variant	6/6	2		ENSP00000446845.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461764 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727170

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2024

The c.2162C>T (p.S721L) alteration is located in exon 7 (coding exon 6) of the ZNF606 gene. This alteration results from a C to T substitution at nucleotide position 2162, causing the serine (S) at amino acid position 721 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	Pathogenic	0.98
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.00072	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.13
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.020	D
Polyphen		0.38	B
Vest4		0.39
MutPred		0.63		Loss of disorder (P = 0.0206);
MVP		0.37
MPC		0.17
ClinPred		0.92	D
GERP RS		3.4
Varity_R		0.35
gMVP		0.11

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-58489886; COSMIC: COSV58708139; COSMIC: COSV58708139;