Genetic Variant ZC2HC1A:p.Ala196Pro (chr8-78697488-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_016010.3(ZC2HC1A):c.586G>C(p.Ala196Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A196D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

ZC2HC1A
NM_016010.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.585

Publications

7 publications found

Variant links:

Genes affected

ZC2HC1A (HGNC:24277): (zinc finger C2HC-type containing 1A) Predicted to enable metal ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ZC2HC1A links:

IL7 (HGNC:6023): (interleukin 7) The protein encoded by this gene is a cytokine important for B and T cell development. This cytokine and the hepatocyte growth factor (HGF) form a heterodimer that functions as a pre-pro-B cell growth-stimulating factor. IL7 is found to be a cofactor for V(D)J rearrangement of the T cell receptor beta (TCRB) during early T cell development. This cytokine can be produced locally by intestinal epithelial and epithelial goblet cells, and may serve as a regulatory factor for intestinal mucosal lymphocytes. IL7 plays an essential role in lymphoid cell survival, and in the maintenance of naive and memory T cells. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional splice variants have been described but their presence in normal tissues has not been confirmed. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can be a potent inducer of proinflammatory cytokines and chemokines which may defend against the infection, but may also mediate destructive lung injury. Elevated serum IL7 levels, together with several other circulating cytokines and chemokines, has been found to be associated with the severity of Coronavirus Disease 19 (COVID-19). [provided by RefSeq, Jul 2020]

IL7 Gene-Disease associations (from GenCC):

epidermodysplasia verruciformis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
epidermodysplasia verruciformis, susceptibility to, 5
Inheritance: AR Classification: LIMITED Submitted by: G2P

IL7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.058938116).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016010.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZC2HC1A	NM_016010.3	MANE Select	c.586G>C	p.Ala196Pro	missense	Exon 6 of 9	NP_057094.2	Q96GY0
ZC2HC1A	NM_001362969.2		c.586G>C	p.Ala196Pro	missense	Exon 6 of 10	NP_001349898.1	H0YAP0
ZC2HC1A	NR_156423.2		n.646G>C		non_coding_transcript_exon	Exon 6 of 11

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZC2HC1A	ENST00000263849.9	TSL:1 MANE Select	c.586G>C	p.Ala196Pro	missense	Exon 6 of 9	ENSP00000263849.3	Q96GY0
ZC2HC1A	ENST00000519307.2	TSL:5	c.586G>C	p.Ala196Pro	missense	Exon 6 of 10	ENSP00000427797.2	H0YAP0
ZC2HC1A	ENST00000874954.1		c.583G>C	p.Ala195Pro	missense	Exon 6 of 9	ENSP00000545013.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.021

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.35

M_CAP

Benign

0.012

MetaRNN

Benign

0.059

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

0.58

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.1

REVEL

Benign

0.046

Sift

Benign

0.20

Sift4G

Benign

0.20

Polyphen

0.095

Vest4

0.24

MutPred

0.17

Loss of catalytic residue at A196 (P = 0.0219)

MVP

0.093

MPC

0.16

ClinPred

0.044

GERP RS

0.38

PromoterAI

0.013

Neutral

(source)

Varity_R

0.13

gMVP

0.27

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over