2-97739787-G-C

Variant names:

• chr2-97739787-G-C
• rs2278699
• ENST00000463643.5:n.2010G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000463643.5(ZAP70):​n.2010G>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 470,936 control chromosomes in the GnomAD database, including 4,247 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1828 hom., cov: 33)
  • Exomes 𝑓: 0.12 (2419 hom.)
• Consequence: ZAP70 ENST00000463643.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.349
• Publications: 10 publications found

Genes affected

ZAP70 (HGNC:12858): (zeta chain of T cell receptor associated protein kinase 70) This gene encodes an enzyme belonging to the protein tyrosine kinase family, and it plays a role in T-cell development and lymphocyte activation. This enzyme, which is phosphorylated on tyrosine residues upon T-cell antigen receptor (TCR) stimulation, functions in the initial step of TCR-mediated signal transduction in combination with the Src family kinases, Lck and Fyn. This enzyme is also essential for thymocyte development. Mutations in this gene cause selective T-cell defect, a severe combined immunodeficiency disease characterized by a selective absence of CD8-positive T-cells. Two transcript variants that encode different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ZAP70 Gene-Disease associations (from GenCC):

• combined immunodeficiency due to ZAP70 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-97739787-G-C is Benign according to our data. Variant chr2-97739787-G-C is described in ClinVar as Benign. ClinVar VariationId is 337642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZAP70	NM_001079.4	c.*289G>C		3_prime_UTR_variant	Exon 14 of 14	ENST00000264972.10	NP_001070.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZAP70	ENST00000264972.10	c.*289G>C		3_prime_UTR_variant	Exon 14 of 14	1	NM_001079.4	ENSP00000264972.5

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21611 AN: 152048 Hom.: 1826 Cov.: 33

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.149

Gnomad SAS AF: 0.0948

Gnomad FIN AF: 0.0529

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.159

GnomAD4 exome AF: 0.116 AC: 37017 AN: 318770 Hom.: 2419 Cov.: 3 AF XY: 0.116 AC XY: 19122 AN XY: 165160

African (AFR) AF: 0.222 AC: 2173 AN: 9794

American (AMR) AF: 0.0932 AC: 1147 AN: 12310

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 1259 AN: 10568

East Asian (EAS) AF: 0.145 AC: 3235 AN: 22386

South Asian (SAS) AF: 0.0991 AC: 2805 AN: 28310

European-Finnish (FIN) AF: 0.0615 AC: 1330 AN: 21618

Middle Eastern (MID) AF: 0.170 AC: 253 AN: 1492

European-Non Finnish (NFE) AF: 0.116 AC: 22402 AN: 192736

Other (OTH) AF: 0.123 AC: 2413 AN: 19556

GnomAD4 genome AF: 0.142 AC: 21620 AN: 152166 Hom.: 1828 Cov.: 33 AF XY: 0.139 AC XY: 10307 AN XY: 74406

African (AFR) AF: 0.226 AC: 9378 AN: 41482

American (AMR) AF: 0.102 AC: 1558 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 471 AN: 3470

East Asian (EAS) AF: 0.148 AC: 767 AN: 5176

South Asian (SAS) AF: 0.0949 AC: 458 AN: 4826

European-Finnish (FIN) AF: 0.0529 AC: 562 AN: 10614

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.115 AC: 7852 AN: 67984

Other (OTH) AF: 0.157 AC: 332 AN: 2114

Alfa AF: 0.128 Hom.: 195

Bravo AF: 0.153

Asia WGS AF: 0.0970 AC: 336 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Combined immunodeficiency due to ZAP70 deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.94
DANN	Benign	0.72
PhyloP100		-0.35
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2278699; hg19: chr2-98356250;