chr3-38307611-C-G

Variant names:

• chr3-38307611-C-G
• rs367799030
• NM_001320033.2:c.666C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001320033.2(SLC22A14):​c.666C>G​(p.Ile222Met) 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 benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC22A14 NM_001320033.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.32

Genes affected

SLC22A14 (HGNC:8495): (solute carrier family 22 member 14) This gene encodes a member of the organic-cation transporter family. It is located in a gene cluster with another member of the family, organic cation transporter like 3. The encoded protein is a transmembrane protein which is thought to transport small molecules and since this protein is conserved among several species, it is suggested to have a fundamental role in mammalian systems. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09606081).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC22A14	NM_001320033.2	c.666C>G	p.Ile222Met	missense_variant	Exon 4 of 11	ENST00000448498.6	NP_001306962.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC22A14	ENST00000448498.6	c.666C>G	p.Ile222Met	missense_variant	Exon 4 of 11	1	NM_001320033.2	ENSP00000396283.1
SLC22A14	ENST00000273173.4	c.666C>G	p.Ile222Met	missense_variant	Exon 3 of 10	1		ENSP00000273173.4
SLC22A14	ENST00000466887.5	c.270C>G	p.Ile90Met	missense_variant	Exon 4 of 4	4		ENSP00000442528.1
SLC22A14	ENST00000496724.1	n.1727C>G		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.666C>G (p.I222M) alteration is located in exon 3 (coding exon 3) of the SLC22A14 gene. This alteration results from a C to G substitution at nucleotide position 666, causing the isoleucine (I) at amino acid position 222 to be replaced by a methionine (M). 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	0.080
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	0.36
DANN	Benign	0.56
DEOGEN2	Benign	0.068	.;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.51	T;.;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.096	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.2	.;L;L
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.080	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.16	T;T;T
Polyphen		0.016	.;B;B
Vest4		0.12, 0.089
MutPred		0.58		.;Loss of catalytic residue at I222 (P = 0.0884);Loss of catalytic residue at I222 (P = 0.0884);
MVP		0.11
MPC		0.15
ClinPred		0.096	T
GERP RS		-3.4
Varity_R		0.10
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs367799030; hg19: chr3-38349102;