Variant chr11-124745666-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006176.3(NRGN):c.179G>A(p.Gly60Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000002 in 1,500,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

NRGN
NM_006176.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.13

Variant links:

Genes affected

NRGN (HGNC:8000): (neurogranin) Neurogranin (NRGN) is the human homolog of the neuron-specific rat RC3/neurogranin gene. This gene encodes a postsynaptic protein kinase substrate that binds calmodulin in the absence of calcium. The NRGN gene contains four exons and three introns. The exons 1 and 2 encode the protein and exons 3 and 4 contain untranslated sequences. It is suggested that the NRGN is a direct target for thyroid hormone in human brain, and that control of expression of this gene could underlay many of the consequences of hypothyroidism on mental states during development as well as in adult subjects. [provided by RefSeq, Jul 2008]

NRGN links:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.108480036).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRGN	NM_006176.3 linkuse as main transcript	c.179G>A	p.Gly60Glu	missense_variant	2/4	ENST00000284292.11	NP_006167.1
NRGN	NM_001126181.2 linkuse as main transcript	c.179G>A	p.Gly60Glu	missense_variant	2/4		NP_001119653.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
NRGN	ENST00000284292.11 linkuse as main transcript	c.179G>A	p.Gly60Glu	missense_variant	2/4	1	NM_006176.3	ENSP00000284292	P1
NRGN	ENST00000412681.2 linkuse as main transcript	c.179G>A	p.Gly60Glu	missense_variant	2/4	1		ENSP00000399591	P1
	ENST00000531241.1 linkuse as main transcript	n.183+249C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

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:

0.00000148

AC:

AN:

1348806

Hom.:

Cov.:

AF XY:

0.00000150

AC XY:

AN XY:

665794

show subpopulations

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:

0.00000188

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152144

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2022

The c.179G>A (p.G60E) alteration is located in exon 2 (coding exon 2) of the NRGN gene. This alteration results from a G to A substitution at nucleotide position 179, causing the glycine (G) at amino acid position 60 to be replaced by a glutamic acid (E). 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

Benign

0.13

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.14

T;T

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.57

.;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.91

D;D;D

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

0.74

N;N

REVEL

Benign

0.041

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.46

T;T

Polyphen

0.010

B;B

Vest4

0.18

MutPred

0.19

Loss of MoRF binding (P = 0.0516);Loss of MoRF binding (P = 0.0516);

MVP

0.043

MPC

1.9

ClinPred

0.99

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.26

gMVP

0.65

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over