chr10-46549425-G-A

Position:

• chr10-46549425-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001385282.1(GPRIN2):​c.1312C>T​(p.Arg438Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,422,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R438Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 77)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: GPRIN2 NM_001385282.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13

Genes affected

GPRIN2 (HGNC:23730): (G protein regulated inducer of neurite outgrowth 2) Predicted to be involved in neuron projection development. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPRIN2	NM_001385282.1	c.1312C>T	p.Arg438Trp	missense_variant	3/3	ENST00000374314.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPRIN2	ENST00000374314.6	c.1312C>T	p.Arg438Trp	missense_variant	3/3		NM_001385282.1	P1
GPRIN2	ENST00000374317.2	c.1312C>T	p.Arg438Trp	missense_variant	3/3	3		P1

Frequencies

GnomAD3 genomes Cov.: 77

GnomAD4 exome AF: 0.0000415 AC: 59 AN: 1422968 Hom.: 0 Cov.: 102 AF XY: 0.0000440 AC XY: 31 AN XY: 704266

Gnomad4 AFR exome AF: 0.0000309

Gnomad4 AMR exome AF: 0.000205

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000260

Gnomad4 SAS exome AF: 0.0000499

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000393

Gnomad4 OTH exome AF: 0.0000341

GnomAD4 genome Cov.: 77

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2022

The c.1312C>T (p.R438W) alteration is located in exon 3 (coding exon 1) of the GPRIN2 gene. This alteration results from a C to T substitution at nucleotide position 1312, causing the arginine (R) at amino acid position 438 to be replaced by a tryptophan (W). 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	0.21
BayesDel_noAF	Benign	-0.58
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T
MetaRNN	Pathogenic	0.85	D;D
PROVEAN	Pathogenic	-6.7	D;D
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Vest4		0.78
gMVP		0.90

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

Other links and lift over

dbSNP: rs374975744; hg19: chr10-47000192; COSMIC: COSV65400565;