14-75070968-G-A

Position:

• chr14-75070968-G-A

Variant summary

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

The NM_024643.4(ZC2HC1C):​c.395G>A​(p.Arg132Gln) 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 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZC2HC1C NM_024643.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.61

Genes affected

ZC2HC1C (HGNC:20354): (zinc finger C2HC-type containing 1C) Predicted to enable metal ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ZC2HC1C (HGNC:):

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=0.18588072).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZC2HC1C	NM_024643.4	c.395G>A	p.Arg132Gln	missense_variant	2/3	ENST00000524913.3	NP_078919.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZC2HC1C	ENST00000524913.3	c.395G>A	p.Arg132Gln	missense_variant	2/3	2	NM_024643.4	ENSP00000435550.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 82 AF XY: 0.00 AC XY: 0 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: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

May 08, 2024

The c.395G>A (p.R132Q) alteration is located in exon 2 (coding exon 1) of the ZC2HC1C gene. This alteration results from a G to A substitution at nucleotide position 395, causing the arginine (R) at amino acid position 132 to be replaced by a glutamine (Q). 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	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.017	T;.;.;.;.
Eigen	Benign	0.073
Eigen_PC	Benign	0.045
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.77	T;T;T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.19	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.9	L;.;.;L;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.82	N;N;D;N;D
REVEL	Benign	0.11
Sift	Uncertain	0.0070	D;D;D;D;D
Sift4G	Benign	0.14	T;T;T;T;T
Polyphen		0.96	D;.;.;.;.
Vest4		0.22
MutPred		0.38		Loss of MoRF binding (P = 0.044);Loss of MoRF binding (P = 0.044);Loss of MoRF binding (P = 0.044);Loss of MoRF binding (P = 0.044);Loss of MoRF binding (P = 0.044);
MVP		0.35
MPC		0.15
ClinPred		0.58	D
GERP RS		3.6
Varity_R		0.13
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-75537671;