Variant 11-124745608-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_006176.3(NRGN):c.121A>G(p.Met41Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NRGN
NM_006176.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.80

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:

ENSG00000255045 (HGNC:58070):

ENSG00000255045 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.75

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRGN	NM_006176.3 link	c.121A>G	p.Met41Val	missense_variant	2/4	ENST00000284292.11	NP_006167.1	Q92686A0A024R3M7
NRGN	NM_001126181.2 link	c.121A>G	p.Met41Val	missense_variant	2/4		NP_001119653.1	Q92686A0A024R3M7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NRGN	ENST00000284292.11 link	c.121A>G	p.Met41Val	missense_variant	2/4	1	NM_006176.3	ENSP00000284292.5	Q92686
NRGN	ENST00000412681.2 link	c.121A>G	p.Met41Val	missense_variant	2/4	1		ENSP00000399591.1	Q92686
ENSG00000255045	ENST00000531241.1 link	n.183+307T>C		intron_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1453864

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723220

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Nov 09, 2023

The c.121A>G (p.M41V) alteration is located in exon 2 (coding exon 2) of the NRGN gene. This alteration results from a A to G substitution at nucleotide position 121, causing the methionine (M) at amino acid position 41 to be replaced by a valine (V). 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

Uncertain

0.41

BayesDel_addAF

Uncertain

0.059

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;T

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

.;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.75

D;D

MetaSVM

Benign

-0.80

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.27

Sift

Uncertain

0.0060

D;D

Sift4G

Uncertain

0.014

D;D

Polyphen

0.96

D;D

Vest4

0.61

MutPred

0.40

Loss of methylation at R38 (P = 0.1068);Loss of methylation at R38 (P = 0.1068);

MVP

0.63

MPC

1.6

ClinPred

0.98

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.49

gMVP

0.96

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over