NM_001012642.3:c.416A>G

Variant names:

• chr15-72167049-T-C
• NM_001012642.3:c.416A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001012642.3(GRAMD2A):​c.416A>G​(p.Lys139Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GRAMD2A NM_001012642.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.30
• Publications: 0 publications found

Genes affected

GRAMD2A (HGNC:27287): (GRAM domain containing 2A) Enables phosphatidylinositol-4,5-bisphosphate binding activity. Involved in endoplasmic reticulum-plasma membrane tethering and regulation of store-operated calcium entry. Located in organelle membrane contact site. Is extrinsic component of cytoplasmic side of plasma membrane and intrinsic component of endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

LOC124903522 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRAMD2A	NM_001012642.3	c.416A>G	p.Lys139Arg	missense_variant	Exon 6 of 12	ENST00000309731.12	NP_001012660.1
LOC124903522	XR_007064706.1	n.1041+2501T>C		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRAMD2A	ENST00000309731.12	c.416A>G	p.Lys139Arg	missense_variant	Exon 6 of 12	1	NM_001012642.3	ENSP00000311657.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.416A>G (p.K139R) alteration is located in exon 6 (coding exon 6) of the GRAMD2 gene. This alteration results from a A to G substitution at nucleotide position 416, causing the lysine (K) at amino acid position 139 to be replaced by an arginine (R). 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	0.092
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;.;D;D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D;D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.53	D;D;D;D
MetaSVM	Benign	-0.53	T
PhyloP100		5.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.8	D;D;D;D
REVEL	Uncertain	0.31
Sift	Benign	0.041	D;D;D;T
Sift4G	Uncertain	0.022	D;D;.;D
Polyphen		0.99	D;.;.;.
Vest4		0.49
MutPred		0.53		Gain of MoRF binding (P = 0.0721);.;.;.;
MVP		0.39
MPC		0.51
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.42
gMVP		0.61
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr15-72459390;