8-32548756-A-C

Position:

• chr8-32548756-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013964.5(NRG1):​c.30A>C​(p.Lys10Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
• Consequence: NRG1 NM_013964.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.112

Genes affected

NRG1 (HGNC:7997): (neuregulin 1) The protein encoded by this gene is a membrane glycoprotein that mediates cell-cell signaling and plays a critical role in the growth and development of multiple organ systems. An extraordinary variety of different isoforms are produced from this gene through alternative promoter usage and splicing. These isoforms are expressed in a tissue-specific manner and differ significantly in their structure, and are classified as types I, II, III, IV, V and VI. Dysregulation of this gene has been linked to diseases such as cancer, schizophrenia, and bipolar disorder (BPD). [provided by RefSeq, Apr 2016]

ACMG classification

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=0.18373874).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRG1	NM_013964.5	c.30A>C	p.Lys10Asn	missense_variant	1/12	ENST00000405005.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRG1	ENST00000405005.8	c.30A>C	p.Lys10Asn	missense_variant	1/12	1	NM_013964.5	A2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 36

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74298

Gnomad4 AFR AF: 0.0000241

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

literature only

Psychiatry Genetics Yale University

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	.;.;.;.;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.75	T;T;T;T;T
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.18	T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.69	N;N;N;N;N
MutationTaster	Benign	1.0	D;D;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.53	N;N;N;N;N
REVEL	Benign	0.10
Sift	Uncertain	0.017	D;D;D;D;D
Sift4G	Benign	0.36	T;T;T;T;T
Polyphen		0.28, 0.11, 0.18	.;B;B;B;B
Vest4		0.22
MutPred		0.28		Loss of methylation at K10 (P = 0.0211);Loss of methylation at K10 (P = 0.0211);Loss of methylation at K10 (P = 0.0211);Loss of methylation at K10 (P = 0.0211);Loss of methylation at K10 (P = 0.0211);
MVP		0.58
MPC		0.26
ClinPred		0.30	T
GERP RS		1.9
Varity_R		0.13
gMVP		0.20

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs367543159; hg19: chr8-32406274;