2-43224675-C-G

Position:

• chr2-43224675-C-G

Variant summary

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

The ENST00000282388.4(ZFP36L2):​c.1129G>C​(p.Ala377Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000721 in 1,387,518 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ZFP36L2 ENST00000282388.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0100

Genes affected

ZFP36L2 (HGNC:1108): (ZFP36 ring finger protein like 2) This gene is a member of the TIS11 family of early response genes. Family members are induced by various agonists such as the phorbol ester TPA and the polypeptide mitogen EGF. The encoded protein contains a distinguishing putative zinc finger domain with a repeating cys-his motif. This putative nuclear transcription factor most likely functions in regulating the response to growth factors. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFP36L2	NM_006887.5	c.1129G>C	p.Ala377Pro	missense_variant	2/2	ENST00000282388.4	NP_008818.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFP36L2	ENST00000282388.4	c.1129G>C	p.Ala377Pro	missense_variant	2/2	1	NM_006887.5	ENSP00000282388	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.21e-7 AC: 1 AN: 1387518 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 690142

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: 9.26e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Nov 30, 2022

The c.1129G>C (p.A377P) alteration is located in exon 2 (coding exon 2) of the ZFP36L2 gene. This alteration results from a G to C substitution at nucleotide position 1129, causing the alanine (A) at amino acid position 377 to be replaced by a proline (P). 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	0.65
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	D;N
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.20
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.17	T
Polyphen		1.0	D
Vest4		0.17
MutPred		0.50		Gain of loop (P = 3e-04);
MVP		0.67
MPC		0.47
ClinPred		0.80	D
GERP RS		3.1
Varity_R		0.59
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1344468585; hg19: chr2-43451814;