chr6-108171601-C-G

Variant names:

• chr6-108171601-C-G
• rs1250714320
• NM_003269.5:c.169C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003269.5(NR2E1):​c.169C>G​(p.Gln57Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NR2E1 NM_003269.5 missense, splice_region
• Scores: Splicing: ADA: 0.6841
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.31
• Publications: 1 publications found

Genes affected

NR2E1 (HGNC:7973): (nuclear receptor subfamily 2 group E member 1) The protein encoded by this gene is an orphan receptor involved in retinal development. The encoded protein also regulates adult neural stem cell proliferation and may be involved in control of aggressive behavior. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2015]

NR2E1 Gene-Disease associations (from GenCC):

• microcephaly

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3705387).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003269.5. 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
	NR2E1	NM_003269.5	MANE Select	c.169C>G	p.Gln57Glu	missense splice_region	Exon 2 of 9	NP_003260.1	B6ZGT9
	NR2E1	NM_001286102.1		c.280C>G	p.Gln94Glu	missense splice_region	Exon 2 of 9	NP_001273031.1	Q9Y466-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR2E1	ENST00000368986.9	TSL:1 MANE Select	c.169C>G	p.Gln57Glu	missense splice_region	Exon 2 of 9	ENSP00000357982.5	Q9Y466-1
	NR2E1	ENST00000368983.3	TSL:2	c.280C>G	p.Gln94Glu	missense splice_region	Exon 2 of 9	ENSP00000357979.3	Q9Y466-2
	NR2E1	ENST00000852831.1		c.169C>G	p.Gln57Glu	missense splice_region	Exon 2 of 9	ENSP00000522890.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461756 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727166

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

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	0.13
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.23
Eigen_PC	Benign	0.067
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.050	N
PhyloP100		7.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.0	N
REVEL	Uncertain	0.45
Sift	Benign	0.38	T
Sift4G	Benign	1.0	T
Polyphen		0.010	B
Vest4		0.60
MutPred		0.39		Gain of ubiquitination at K53 (P = 0.0381)
MVP		0.74
MPC		1.9
ClinPred		0.80	D
GERP RS		5.2
Varity_R		0.26
gMVP		0.89
Mutation Taster		=23/77	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.68
dbscSNV1_RF	Benign	0.41
SpliceAI score (max)		0.010		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: rs1250714320; hg19: chr6-108492805;