8-1548974-A-G

Variant summary

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

The NM_001346810.2(DLGAP2):c.521A>G(p.Asp174Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,446,832 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D174N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DLGAP2 NM_001346810.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.59

Genes affected

DLGAP2 (HGNC:2906): (DLG associated protein 2) The product of this gene is a membrane-associated protein that may play a role in synapse organization and signalling in neuronal cells. This gene is biallelically expressed in the brain, however, only the paternal allele is expressed in the testis (PMID:18055845). Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jun 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DLGAP2	NM_001346810.2	c.521A>G	p.Asp174Gly	missense_variant	5/15	ENST00000637795.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DLGAP2	ENST00000637795.2	c.521A>G	p.Asp174Gly	missense_variant	5/15	5	NM_001346810.2
DLGAP2	ENST00000520901.5	c.332A>G	p.Asp111Gly	missense_variant	1/10	1
DLGAP2	ENST00000421627.7	c.518A>G	p.Asp173Gly	missense_variant	5/15	5
DLGAP2	ENST00000612087.1	c.281A>G	p.Asp94Gly	missense_variant	2/11	5		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1446832 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 720292

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Sep 28, 2023

The c.281A>G (p.D94G) alteration is located in exon 2 (coding exon 1) of the DLGAP2 gene. This alteration results from a A to G substitution at nucleotide position 281, causing the aspartic acid (D) at amino acid position 94 to be replaced by a glycine (G). 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	0.12
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.47	T;T;T
MetaSVM	Benign	-0.60	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.61	T
Polyphen		0.98	.;D;.
Vest4		0.84
MutPred		0.45		.;Gain of catalytic residue at D173 (P = 0.0068);.;
MVP		0.22
MPC		0.16
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.27
gMVP		0.43

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.

Other links and lift over

hg19: chr8-1497140;