2-27440840-C-G

Variant names:

• chr2-27440840-C-G
• rs1458643486
• NM_013392.4:c.1229C>G

Variant summary

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

The NM_013392.4(NRBP1):​c.1229C>G​(p.Pro410Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,772 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P410L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NRBP1 NM_013392.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.71
• Publications: 0 publications found

Genes affected

NRBP1 (HGNC:7993): (nuclear receptor binding protein 1) Predicted to enable protein homodimerization activity. Involved in endoplasmic reticulum to Golgi vesicle-mediated transport. Located in endomembrane system. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013392.4. 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
	NRBP1	NM_013392.4	MANE Select	c.1229C>G	p.Pro410Arg	missense	Exon 14 of 18	NP_037524.1	Q9UHY1
	NRBP1	NM_001321358.2		c.1253C>G	p.Pro418Arg	missense	Exon 15 of 19	NP_001308287.1	F8W6G1
	NRBP1	NM_001321359.2		c.1253C>G	p.Pro418Arg	missense	Exon 15 of 19	NP_001308288.1	F8W6G1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRBP1	ENST00000379852.8	TSL:1 MANE Select	c.1229C>G	p.Pro410Arg	missense	Exon 14 of 18	ENSP00000369181.3	Q9UHY1
	NRBP1	ENST00000379863.7	TSL:5	c.1253C>G	p.Pro418Arg	missense	Exon 15 of 19	ENSP00000369192.3	F8W6G1
	NRBP1	ENST00000857545.1		c.1253C>G	p.Pro418Arg	missense	Exon 15 of 19	ENSP00000527604.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461772 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727198

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: 53302

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

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

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.24
Sift	Benign	0.053	T
Sift4G	Benign	0.12	T
Polyphen		0.057	B
Vest4		0.65
MutPred		0.30		Gain of solvent accessibility (P = 0.0055)
MVP		0.62
MPC		1.2
ClinPred		0.96	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.32
gMVP		0.52
Mutation Taster		=24/76	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1458643486; hg19: chr2-27663707;