19-49290376-C-G

Variant names:

• chr19-49290376-C-G
• rs368464579
• NM_014037.3:c.1958G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014037.3(SLC6A16):​c.1958G>C​(p.Arg653Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,654 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. R653Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SLC6A16 NM_014037.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.168
• Publications: 0 publications found

Genes affected

SLC6A16 (HGNC:13622): (solute carrier family 6 member 16) SLC6A16 shows structural characteristics of an Na(+)- and Cl(-)-dependent neurotransmitter transporter, including 12 transmembrane (TM) domains, intracellular N and C termini, and large extracellular loops containing multiple N-glycosylation sites.[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014037.3. 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
	SLC6A16	NM_014037.3	MANE Select	c.1958G>C	p.Arg653Pro	missense	Exon 12 of 12	NP_054756.2	Q9GZN6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC6A16	ENST00000335875.9	TSL:5 MANE Select	c.1958G>C	p.Arg653Pro	missense	Exon 12 of 12	ENSP00000338627.3	Q9GZN6-1
	SLC6A16	ENST00000454748.7	TSL:1	c.*190G>C		3_prime_UTR	Exon 11 of 11	ENSP00000404022.2	Q9GZN6-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460654 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726464

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26008

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111226

Other (OTH) AF: 0.00 AC: 0 AN: 60340

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.020	T
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		-0.17
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.42
Sift	Benign	0.072	T
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.50
MutPred		0.69		Gain of catalytic residue at R653 (P = 0.0379)
MVP		0.76
MPC		0.88
ClinPred		0.97	D
GERP RS		0.21
Varity_R		0.82
gMVP		0.61
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.29		Position offset: 16

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs368464579; hg19: chr19-49793633;