rs2273890

Positions:

• chr1-231795302-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_018662.3(DISC1):​c.1689+6T>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 1,609,354 control chromosomes in the GnomAD database, including 13,975 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 0.12 (1218 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12757 hom.)
• Consequence: DISC1 NM_018662.3 splice_donor_region, intron
• Scores: Splicing: ADA: 0.1883
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.50

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DISC1	NM_018662.3	c.1689+6T>C		splice_donor_region_variant, intron_variant		ENST00000439617.8
TSNAX-DISC1	NR_028393.1	n.2356-4806T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DISC1	ENST00000439617.8	c.1689+6T>C		splice_donor_region_variant, intron_variant		5	NM_018662.3	A2
	ENST00000651424.1	n.259-7959A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18548 AN: 152092 Hom.: 1214 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.275

Gnomad AMR AF: 0.0887

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.0671

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.115

GnomAD3 exomes AF: 0.115 AC: 28597 AN: 247988 Hom.: 1830 AF XY: 0.115 AC XY: 15417 AN XY: 134356

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.0791

Gnomad ASJ exome AF: 0.117

Gnomad EAS exome AF: 0.118

Gnomad SAS exome AF: 0.0650

Gnomad FIN exome AF: 0.128

Gnomad NFE exome AF: 0.138

Gnomad OTH exome AF: 0.106

GnomAD4 exome AF: 0.130 AC: 188813 AN: 1457146 Hom.: 12757 Cov.: 30 AF XY: 0.128 AC XY: 92653 AN XY: 725198

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.0797

Gnomad4 ASJ exome AF: 0.116

Gnomad4 EAS exome AF: 0.116

Gnomad4 SAS exome AF: 0.0674

Gnomad4 FIN exome AF: 0.123

Gnomad4 NFE exome AF: 0.139

Gnomad4 OTH exome AF: 0.120

GnomAD4 genome AF: 0.122 AC: 18570 AN: 152208 Hom.: 1218 Cov.: 32 AF XY: 0.119 AC XY: 8883 AN XY: 74398

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.0888

Gnomad4 ASJ AF: 0.121

Gnomad4 EAS AF: 0.117

Gnomad4 SAS AF: 0.0667

Gnomad4 FIN AF: 0.124

Gnomad4 NFE AF: 0.138

Gnomad4 OTH AF: 0.117

Alfa AF: 0.128 Hom.: 645

Bravo AF: 0.122

Asia WGS AF: 0.0800 AC: 278 AN: 3478

EpiCase AF: 0.135

EpiControl AF: 0.129

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	16
DANN	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.19
dbscSNV1_RF	Benign	0.29
SpliceAI score (max)		0.090		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: rs2273890; hg19: chr1-231931048; COSMIC: COSV54408055;