12-20717191-T-A

Position:

• chr12-20717191-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000266509.7(SLCO1C1):​c.736T>A​(p.Cys246Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,447,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLCO1C1 ENST00000266509.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.64

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLCO1C1	NM_017435.5	c.736T>A	p.Cys246Ser	missense_variant	7/15	ENST00000266509.7	NP_059131.1
SLCO1C1	NM_001145946.2	c.736T>A	p.Cys246Ser	missense_variant	8/16		NP_001139418.1
SLCO1C1	NM_001145945.2	c.589T>A	p.Cys197Ser	missense_variant	7/15		NP_001139417.1
SLCO1C1	NM_001145944.2	c.382T>A	p.Cys128Ser	missense_variant	5/13		NP_001139416.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLCO1C1	ENST00000266509.7	c.736T>A	p.Cys246Ser	missense_variant	7/15	1	NM_017435.5	ENSP00000266509	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1447754 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 719866

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2023

The c.736T>A (p.C246S) alteration is located in exon 8 (coding exon 6) of the SLCO1C1 gene. This alteration results from a T to A substitution at nucleotide position 736, causing the cysteine (C) at amino acid position 246 to be replaced by a serine (S). 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	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.058	.;T;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;T;T;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.6	.;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.8	D;D;D;D
REVEL	Pathogenic	0.69
Sift	Benign	0.050	D;T;D;D
Sift4G	Uncertain	0.060	T;T;D;T
Polyphen		0.89	.;P;.;.
Vest4		0.93
MutPred		0.69		.;Gain of catalytic residue at S244 (P = 0);Gain of catalytic residue at S244 (P = 0);.;
MVP		0.78
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.65
gMVP		0.85

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-20870125;