rs199777356

Variant names:

• chr1-10451504-G-A
• rs199777356
• NM_001302.5:c.227G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-10451504-G-A
• chr1-10451504-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001302.5(CORT):​c.227G>A​(p.Arg76Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00023 in 1,613,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: CORT NM_001302.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.76
• Publications: 0 publications found

Genes affected

CORT (HGNC:2257): (cortistatin) This gene encodes a neuropeptide that is structurally similar to somatostatin. It binds to all known somatostatin receptors, and shares many pharmacological and functional properties with somatostatin, including the depression of neuronal activity. However, it also has many properties distinct from somatostatin, such as induction of slow-wave sleep, apparently by antagonism of the excitatory effects of acetylcholine on the cortex, reduction of locomotor activity, and activation of cation selective currents not responsive to somatostatin. The preproprotein undergoes further processing into multiple mature products. Read-through transcripts exist between this gene and the upstream APITD1 (apoptosis-inducing, TAF9-like domain 1) gene, as represented in GeneID:100526739. [provided by RefSeq, Nov 2010]

CENPS-CORT (HGNC:38843): (CENPS-CORT readthrough) This locus represents naturally occurring read-through transcription between the neighboring APITD1 (apoptosis-inducing, TAF9-like domain 1) and CORT (cortistatin) genes. Alternative splicing results in multiple transcript variants, two of which encode fusion proteins that share sequence identity with the products of each individual gene. [provided by RefSeq, Aug 2011]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.109173894).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001302.5. 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
	CORT	NM_001302.5	MANE Select	c.227G>A	p.Arg76Gln	missense	Exon 2 of 2	NP_001293.3
	CENPS-CORT	NM_198544.4		c.404G>A	p.Arg135Gln	missense	Exon 5 of 5	NP_940946.1
	CENPS-CORT	NM_001243768.2		c.341G>A	p.Arg114Gln	missense	Exon 4 of 4	NP_001230697.1	A0A087WT10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CORT	ENST00000377049.4	TSL:1 MANE Select	c.227G>A	p.Arg76Gln	missense	Exon 2 of 2	ENSP00000366248.4	O00230
	CENPS-CORT	ENST00000400900.6	TSL:2	c.404G>A	p.Arg135Gln	missense	Exon 5 of 5	ENSP00000383692.2
	CENPS-CORT	ENST00000602296.6	TSL:3	c.341G>A	p.Arg114Gln	missense	Exon 4 of 4	ENSP00000473401.2	A0A087WT10

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000931 AC: 23 AN: 247140 AF XY: 0.000104

Gnomad AFR exome AF: 0.0000645

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000190

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000237 AC: 347 AN: 1461734 Hom.: 0 Cov.: 68 AF XY: 0.000232 AC XY: 169 AN XY: 727166

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5750

European-Non Finnish (NFE) AF: 0.000289 AC: 321 AN: 1111972

Other (OTH) AF: 0.000298 AC: 18 AN: 60378

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152176 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74352

African (AFR) AF: 0.0000965 AC: 4 AN: 41442

American (AMR) AF: 0.0000655 AC: 1 AN: 15266

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

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: 0.000294 AC: 20 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000203 Hom.: 0

Bravo AF: 0.000136

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000164

EpiControl AF: 0.00

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	0.086
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.8
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.073
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.22	T
Polyphen		1.0	D
Vest4		0.16
MVP		0.014
MPC		0.16
ClinPred		0.14	T
GERP RS		5.8
Varity_R		0.22
gMVP		0.049
Mutation Taster		=91/9	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: rs199777356; hg19: chr1-10511561; COSMIC: COSV57630587; COSMIC: COSV57630587;