chr8-26627930-G-T

Variant names:

• chr8-26627930-G-T
• rs771070678
• NM_001197293.3:c.995G>T

Variant summary

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

The NM_001197293.3(DPYSL2):​c.995G>T​(p.Arg332Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: DPYSL2 NM_001197293.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.81

Genes affected

DPYSL2 (HGNC:3014): (dihydropyrimidinase like 2) This gene encodes a member of the collapsin response mediator protein family. Collapsin response mediator proteins form homo- and hetero-tetramers and facilitate neuron guidance, growth and polarity. The encoded protein promotes microtubule assembly and is required for Sema3A-mediated growth cone collapse, and also plays a role in synaptic signaling through interactions with calcium channels. This gene has been implicated in multiple neurological disorders, and hyperphosphorylation of the encoded protein may play a key role in the development of Alzheimer's disease. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Sep 2011]

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, 0.904

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPYSL2	NM_001197293.3	c.995G>T	p.Arg332Leu	missense_variant	Exon 7 of 14	ENST00000521913.7	NP_001184222.1
DPYSL2	NM_001386.6	c.680G>T	p.Arg227Leu	missense_variant	Exon 7 of 14		NP_001377.1
DPYSL2	NM_001244604.2	c.572G>T	p.Arg191Leu	missense_variant	Exon 7 of 14		NP_001231533.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPYSL2	ENST00000521913.7	c.995G>T	p.Arg332Leu	missense_variant	Exon 7 of 14	1	NM_001197293.3	ENSP00000427985.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74348

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	.;D;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	.;H;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.9	.;D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	.;D;D
Sift4G	Uncertain	0.0030	.;D;D
Polyphen		0.87	.;P;.
Vest4		0.86
MutPred		0.67		.;Loss of disorder (P = 0.0614);.;
MVP		0.95
MPC		2.2
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.98
gMVP		0.98

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

Publications

LitVar

Other links and lift over

dbSNP: rs771070678; hg19: chr8-26485446;