rs12133766

chr1-231818399-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_018662.3(DISC1):c.1863G>A(p.Leu621=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0549 in 1,614,106 control chromosomes in the GnomAD database, including 2,695 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.046 (188 hom., cov: 33)
  • Exomes 𝑓: 0.056 (2507 hom.)
• Consequence: DISC1 NM_018662.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.46

Genes affected

DISC1 (HGNC:2888): (DISC1 scaffold protein) This gene encodes a protein with multiple coiled coil motifs which is located in the nucleus, cytoplasm and mitochondria. The protein is involved in neurite outgrowth and cortical development through its interaction with other proteins. This gene is disrupted in a t(1;11)(q42.1;q14.3) translocation which segregates with schizophrenia and related psychiatric disorders in a large Scottish family. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

DISC2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP7: Synonymous conserved (PhyloP=3.46 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DISC1	NM_018662.3	c.1863G>A	p.Leu621=	synonymous_variant	9/13	ENST00000439617.8
DISC2	NR_002227.2	n.119C>T		non_coding_transcript_exon_variant	1/1
TSNAX-DISC1	NR_028393.1	n.2529G>A		non_coding_transcript_exon_variant	12/16
LOC105373170	XR_949268.4	n.296-4108C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DISC1	ENST00000439617.8	c.1863G>A	p.Leu621=	synonymous_variant	9/13	5	NM_018662.3	A2
	ENST00000651424.1	n.258+4326C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0458 AC: 6975 AN: 152168 Hom.: 188 Cov.: 33

Gnomad AFR AF: 0.0183

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0463

Gnomad ASJ AF: 0.0919

Gnomad EAS AF: 0.0327

Gnomad SAS AF: 0.0518

Gnomad FIN AF: 0.0663

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0576

Gnomad OTH AF: 0.0527

GnomAD3 exomes AF: 0.0502 AC: 12616 AN: 251278 Hom.: 386 AF XY: 0.0525 AC XY: 7130 AN XY: 135792

Gnomad AFR exome AF: 0.0181

Gnomad AMR exome AF: 0.0283

Gnomad ASJ exome AF: 0.0833

Gnomad EAS exome AF: 0.0293

Gnomad SAS exome AF: 0.0457

Gnomad FIN exome AF: 0.0577

Gnomad NFE exome AF: 0.0613

Gnomad OTH exome AF: 0.0577

GnomAD4 exome AF: 0.0558 AC: 81611 AN: 1461820 Hom.: 2507 Cov.: 31 AF XY: 0.0563 AC XY: 40928 AN XY: 727220

Gnomad4 AFR exome AF: 0.0174

Gnomad4 AMR exome AF: 0.0292

Gnomad4 ASJ exome AF: 0.0876

Gnomad4 EAS exome AF: 0.0231

Gnomad4 SAS exome AF: 0.0464

Gnomad4 FIN exome AF: 0.0543

Gnomad4 NFE exome AF: 0.0590

Gnomad4 OTH exome AF: 0.0587

GnomAD4 genome AF: 0.0458 AC: 6981 AN: 152286 Hom.: 188 Cov.: 33 AF XY: 0.0462 AC XY: 3444 AN XY: 74474

Gnomad4 AFR AF: 0.0184

Gnomad4 AMR AF: 0.0462

Gnomad4 ASJ AF: 0.0919

Gnomad4 EAS AF: 0.0328

Gnomad4 SAS AF: 0.0520

Gnomad4 FIN AF: 0.0663

Gnomad4 NFE AF: 0.0576

Gnomad4 OTH AF: 0.0521

Alfa AF: 0.0591 Hom.: 463

Bravo AF: 0.0436

Asia WGS AF: 0.0400 AC: 138 AN: 3478

EpiCase AF: 0.0667

EpiControl AF: 0.0652

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	9.0
Dann	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs12133766; hg19: chr1-231954145; COSMIC: COSV54403519; COSMIC: COSV54403519;