14-21001335-T-C

Variant names:

• chr14-21001335-T-C
• NM_014579.4:c.686T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_014579.4(SLC39A2):​c.686T>C​(p.Leu229Pro) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC39A2 NM_014579.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.74

Genes affected

SLC39A2 (HGNC:17127): (solute carrier family 39 member 2) This gene encodes a member of the ZIP family of metal ion transporters. The encoded protein functions as a zinc transporter. Mutations in this gene may be associated with susceptibility to carotid artery disease. Multiple transcript variants have been described. [provided by RefSeq, Mar 2010]

ENSG00000258471 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC39A2	NM_014579.4	c.686T>C	p.Leu229Pro	missense_variant	Exon 4 of 4	ENST00000298681.5	NP_055394.2
SLC39A2	NM_001256588.2	c.*423T>C		3_prime_UTR_variant	Exon 4 of 4		NP_001243517.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC39A2	ENST00000298681.5	c.686T>C	p.Leu229Pro	missense_variant	Exon 4 of 4	1	NM_014579.4	ENSP00000298681.4
SLC39A2	ENST00000554422.5	c.*423T>C		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000452568.1
ENSG00000258471	ENST00000647921.1	n.398-1505A>G		intron_variant	Intron 1 of 4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.686T>C (p.L229P) alteration is located in exon 4 (coding exon 4) of the SLC39A2 gene. This alteration results from a T to C substitution at nucleotide position 686, causing the leucine (L) at amino acid position 229 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	Benign	0.31
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.064
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.098	T
MutationAssessor	Pathogenic	3.3	M
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.98	D
Vest4		0.71
MutPred		0.85		Loss of stability (P = 0.0251);
MVP		0.55
MPC		0.29
ClinPred		0.96	D
GERP RS		5.8
Varity_R		0.96
gMVP		0.89

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: chr14-21469494;