1-26044435-A-G

Variant names:

• chr1-26044435-A-G
• NM_001004434.3:c.281T>C

Variant summary

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

The NM_001004434.3(SLC30A2):​c.281T>C​(p.Leu94Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L94V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC30A2 NM_001004434.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.47
• Publications: 0 publications found

Genes affected

SLC30A2 (HGNC:11013): (solute carrier family 30 member 2) The protein encoded by this gene is a zinc transporter that acts as a homodimer. The encoded protein plays a role in secreting zinc into breast milk. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2015]

SLC30A2 Gene-Disease associations (from GenCC):

• zinc deficiency, transient neonatal

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, ClinGen

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, 0.959

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001004434.3. 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
	SLC30A2	NM_001004434.3	MANE Select	c.281T>C	p.Leu94Pro	missense	Exon 3 of 8	NP_001004434.1	Q9BRI3-2
	SLC30A2	NM_032513.5		c.271+562T>C		intron	N/A	NP_115902.1	Q9BRI3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC30A2	ENST00000374276.4	TSL:1 MANE Select	c.281T>C	p.Leu94Pro	missense	Exon 3 of 8	ENSP00000363394.3	Q9BRI3-2
	SLC30A2	ENST00000374278.7	TSL:1	c.271+562T>C		intron	N/A	ENSP00000363396.3	Q9BRI3-1
	SLC30A2	ENST00000946935.1		c.281T>C	p.Leu94Pro	missense	Exon 3 of 8	ENSP00000616994.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	31
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.45	D
PhyloP100		7.5
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.83		Gain of relative solvent accessibility (P = 0.1571)
MVP		0.38
MPC		1.3
ClinPred		1.0	D
GERP RS		5.7
gMVP		0.97
Mutation Taster		=30/70	disease causing

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

Other links and lift over

hg19: chr1-26370926;