12-20706047-C-G

Variant names:

• chr12-20706047-C-G
• rs373359001
• NM_017435.5:c.370C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017435.5(SLCO1C1):​c.370C>G​(p.Leu124Val) 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 1,460,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SLCO1C1 NM_017435.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.565
• Publications: 2 publications found

Genes affected

SLCO1C1 (HGNC:13819): (solute carrier organic anion transporter family member 1C1) This gene encodes a member of the organic anion transporter family. The encoded protein is a transmembrane receptor that mediates the sodium-independent uptake of thyroid hormones in brain tissues. This protein has particularly high affinity for the thyroid hormones thyroxine, tri-iodothyronine and reverse tri-iodothyronine. Polymorphisms in the gene encoding this protein may be associated with fatigue and depression in patients suffering from hyperthyroidism. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2009]

SLCO1C1 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06915873).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017435.5. 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
	SLCO1C1	NM_017435.5	MANE Select	c.370C>G	p.Leu124Val	missense	Exon 4 of 15	NP_059131.1	Q9NYB5-1
	SLCO1C1	NM_001145946.2		c.370C>G	p.Leu124Val	missense	Exon 5 of 16	NP_001139418.1	Q9NYB5-3
	SLCO1C1	NM_001145945.2		c.370C>G	p.Leu124Val	missense	Exon 5 of 15	NP_001139417.1	Q9NYB5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLCO1C1	ENST00000266509.7	TSL:1 MANE Select	c.370C>G	p.Leu124Val	missense	Exon 4 of 15	ENSP00000266509.2	Q9NYB5-1
	SLCO1C1	ENST00000539415.5	TSL:1	n.130-5339C>G		intron	N/A	ENSP00000437399.1	F5H6S4
	SLCO1C1	ENST00000545604.5	TSL:2	c.370C>G	p.Leu124Val	missense	Exon 5 of 16	ENSP00000444149.1	Q9NYB5-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 250810 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460922 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726744

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111388

Other (OTH) AF: 0.0000166 AC: 1 AN: 60358

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.014
DANN	Benign	0.77
DEOGEN2	Benign	0.0029	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.56
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.078
Sift	Benign	0.49	T
Sift4G	Benign	0.24	T
Polyphen		0.0010	B
Vest4		0.33
MutPred		0.58		Gain of catalytic residue at G120 (P = 0)
MVP		0.12
ClinPred		0.032	T
GERP RS		-10
Varity_R		0.034
gMVP		0.67
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs373359001; hg19: chr12-20858981; COSMIC: COSV56869679;