chr14-21001140-G-C

Variant names:

• chr14-21001140-G-C
• rs138590006
• NM_014579.4:c.491G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_014579.4(SLC39A2):​c.491G>C​(p.Arg164Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R164Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC39A2 NM_014579.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.09
• Publications: 3 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014579.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC39A2	NM_014579.4	MANE Select	c.491G>C	p.Arg164Pro	missense	Exon 4 of 4	NP_055394.2	Q9NP94-1
	SLC39A2	NM_001256588.2		c.*228G>C		3_prime_UTR	Exon 4 of 4	NP_001243517.1	Q9NP94-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC39A2	ENST00000298681.5	TSL:1 MANE Select	c.491G>C	p.Arg164Pro	missense	Exon 4 of 4	ENSP00000298681.4	Q9NP94-1
	SLC39A2	ENST00000554422.5	TSL:1	c.*228G>C		3_prime_UTR	Exon 4 of 4	ENSP00000452568.1	Q9NP94-2
	ENSG00000258471	ENST00000647921.1		n.398-1310C>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	3.7	H
PhyloP100		9.1
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.76		Gain of glycosylation at R164 (P = 0.0135)
MVP		0.75
MPC		0.29
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.88
Mutation Taster		=61/39	polymorphism

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: rs138590006; hg19: chr14-21469299;