rs111814314

Variant names:

• chr12-95049167-C-T
• rs111814314
• NM_003297.4:c.1032G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_003297.4(NR2C1):​c.1032G>A​(p.Ala344Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0046 in 1,614,050 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0036 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (35 hom.)
• Consequence: NR2C1 NM_003297.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0220
• Publications: 2 publications found

Genes affected

NR2C1 (HGNC:7971): (nuclear receptor subfamily 2 group C member 1) This gene encodes a nuclear hormone receptor characterized by a highly conserved DNA binding domain (DBD), a variable hinge region, and a carboxy-terminal ligand binding domain (LBD) that is typical for all members of the steroid/thyroid hormone receptor superfamily. This protein also belongs to a large family of ligand-inducible transcription factors that regulate gene expression by binding to specific DNA sequences within promoters of target genes. Multiple alternatively spliced transcript variants have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 12-95049167-C-T is Benign according to our data. Variant chr12-95049167-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2643220.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.022 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 35 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003297.4. 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
	NR2C1	NM_003297.4	MANE Select	c.1032G>A	p.Ala344Ala	synonymous	Exon 9 of 14	NP_003288.2	P13056-1
	NR2C1	NM_001127362.2		c.1032G>A	p.Ala344Ala	synonymous	Exon 9 of 12	NP_001120834.1	P13056-3
	NR2C1	NM_001032287.3		c.1032G>A	p.Ala344Ala	synonymous	Exon 9 of 12	NP_001027458.1	H9NIM3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR2C1	ENST00000333003.10	TSL:2 MANE Select	c.1032G>A	p.Ala344Ala	synonymous	Exon 9 of 14	ENSP00000333275.4	P13056-1
	NR2C1	ENST00000393101.7	TSL:1	c.1032G>A	p.Ala344Ala	synonymous	Exon 9 of 12	ENSP00000376813.3	P13056-2
	NR2C1	ENST00000545833.5	TSL:1	n.1032G>A		non_coding_transcript_exon	Exon 8 of 10

Frequencies

GnomAD3 genomes AF: 0.00365 AC: 555 AN: 152150 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00289

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00606

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00388 AC: 976 AN: 251464 AF XY: 0.00362

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00468

Gnomad ASJ exome AF: 0.00367

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00589

Gnomad OTH exome AF: 0.00635

GnomAD4 exome AF: 0.00470 AC: 6873 AN: 1461784 Hom.: 35 Cov.: 31 AF XY: 0.00461 AC XY: 3349 AN XY: 727212

African (AFR) AF: 0.00108 AC: 36 AN: 33478

American (AMR) AF: 0.00461 AC: 206 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00268 AC: 70 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00139 AC: 120 AN: 86252

European-Finnish (FIN) AF: 0.00101 AC: 54 AN: 53420

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.00553 AC: 6147 AN: 1111920

Other (OTH) AF: 0.00369 AC: 223 AN: 60388

GnomAD4 genome AF: 0.00364 AC: 555 AN: 152266 Hom.: 1 Cov.: 32 AF XY: 0.00352 AC XY: 262 AN XY: 74444

African (AFR) AF: 0.000818 AC: 34 AN: 41546

American (AMR) AF: 0.00321 AC: 49 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4830

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00606 AC: 412 AN: 68028

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00460 Hom.: 0

Bravo AF: 0.00345

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00529

EpiControl AF: 0.00676

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	12
DANN	Benign	0.38
PhyloP100		0.022
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs111814314; hg19: chr12-95442943; COSMIC: COSV58010380;