6-143884359-T-A

Variant names:

• chr6-143884359-T-A
• rs904252197
• NM_001013623.3:c.84T>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001013623.3(ZC2HC1B):​c.84T>A​(p.Asp28Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000197 in 152,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 32)
• Consequence: ZC2HC1B NM_001013623.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.57

Genes affected

ZC2HC1B (HGNC:21174): (zinc finger C2HC-type containing 1B) Predicted to enable metal ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000280148 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3253131).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZC2HC1B	NM_001013623.3	c.84T>A	p.Asp28Glu	missense_variant	Exon 2 of 8	ENST00000237275.9	NP_001013645.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZC2HC1B	ENST00000237275.9	c.84T>A	p.Asp28Glu	missense_variant	Exon 2 of 8	1	NM_001013623.3	ENSP00000237275.6
ENSG00000280148	ENST00000454207.2	n.*28T>A		non_coding_transcript_exon_variant	Exon 4 of 10	2		ENSP00000400756.2
ZC2HC1B	ENST00000539295.3	n.271T>A		non_coding_transcript_exon_variant	Exon 3 of 9	1
ENSG00000280148	ENST00000454207.2	n.*28T>A		3_prime_UTR_variant	Exon 4 of 10	2		ENSP00000400756.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152244 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000723

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74376

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.84T>A (p.D28E) alteration is located in exon 2 (coding exon 2) of the ZC2HC1B gene. This alteration results from a T to A substitution at nucleotide position 84, causing the aspartic acid (D) at amino acid position 28 to be replaced by a glutamic acid (E). 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	Benign	0.18
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.8	L
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.076
Sift	Benign	0.32	T
Sift4G	Benign	1.0	T
Polyphen		0.78	P
Vest4		0.52
MutPred		0.30		Gain of disorder (P = 0.1025);
MVP		0.22
ClinPred		0.93	D
GERP RS		5.2
Varity_R		0.18
gMVP		0.13

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: rs904252197; hg19: chr6-144205496;