1-231770843-C-T

Variant names:

• chr1-231770843-C-T
• rs2492367
• NM_018662.3:c.1407C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_018662.3(DISC1):​c.1407C>T​(p.Ile469Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,613,658 control chromosomes in the GnomAD database, including 12,130 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 0.14 (1509 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10621 hom.)
• Consequence: DISC1 NM_018662.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.85
• Publications: 30 publications found

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]

TSNAX-DISC1 (HGNC:49177): (TSNAX-DISC1 readthrough (NMD candidate)) This gene represents naturally occurring read-through transcription between the neighboring TSNAX (translin-associated factor X) and DISC1 (disrupted in schizophrenia 1) genes on chromosome 1. Alternative splicing results in multiple transcript variants, all of which are candidates for nonsense-mediated mRNA decay (NMD) and are unlikely to be protein-coding. These alterations in gene processing may be associated with risk for psychiatric illness, most notably, schizophrenia. [provided by RefSeq, Nov 2010]

ENSG00000286071 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001459837).
• BP7: Synonymous conserved (PhyloP=-1.85 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DISC1	NM_018662.3	c.1407C>T	p.Ile469Ile	synonymous_variant	Exon 6 of 13	ENST00000439617.8	NP_061132.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DISC1	ENST00000439617.8	c.1407C>T	p.Ile469Ile	synonymous_variant	Exon 6 of 13	5	NM_018662.3	ENSP00000403888.4
DISC1	ENST00000366637.8	c.1407C>T	p.Ile469Ile	synonymous_variant	Exon 6 of 13	5		ENSP00000355597.6
TSNAX-DISC1	ENST00000602956.5	n.*1268C>T		non_coding_transcript_exon_variant	Exon 10 of 13	2		ENSP00000473532.1
TSNAX-DISC1	ENST00000602956.5	n.*1268C>T		3_prime_UTR_variant	Exon 10 of 13	2		ENSP00000473532.1

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20564 AN: 152058 Hom.: 1507 Cov.: 32

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.0976

Gnomad AMR AF: 0.0737

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.143

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.0867

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.138

GnomAD2 exomes AF: 0.116 AC: 28701 AN: 247762 AF XY: 0.117

Gnomad AFR exome AF: 0.205

Gnomad AMR exome AF: 0.0528

Gnomad ASJ exome AF: 0.125

Gnomad EAS exome AF: 0.150

Gnomad FIN exome AF: 0.0903

Gnomad NFE exome AF: 0.118

Gnomad OTH exome AF: 0.104

GnomAD4 exome AF: 0.118 AC: 171799 AN: 1461482 Hom.: 10621 Cov.: 33 AF XY: 0.118 AC XY: 86119 AN XY: 727016

African (AFR) AF: 0.204 AC: 6844 AN: 33476

American (AMR) AF: 0.0562 AC: 2513 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 3344 AN: 26122

East Asian (EAS) AF: 0.114 AC: 4529 AN: 39694

South Asian (SAS) AF: 0.131 AC: 11310 AN: 86200

European-Finnish (FIN) AF: 0.0941 AC: 5027 AN: 53398

Middle Eastern (MID) AF: 0.114 AC: 660 AN: 5768

European-Non Finnish (NFE) AF: 0.117 AC: 130073 AN: 1111764

Other (OTH) AF: 0.124 AC: 7499 AN: 60384

GnomAD4 genome AF: 0.135 AC: 20606 AN: 152176 Hom.: 1509 Cov.: 32 AF XY: 0.131 AC XY: 9762 AN XY: 74388

African (AFR) AF: 0.200 AC: 8294 AN: 41482

American (AMR) AF: 0.0736 AC: 1126 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 426 AN: 3472

East Asian (EAS) AF: 0.143 AC: 741 AN: 5180

South Asian (SAS) AF: 0.124 AC: 599 AN: 4830

European-Finnish (FIN) AF: 0.0867 AC: 919 AN: 10598

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.119 AC: 8069 AN: 68002

Other (OTH) AF: 0.142 AC: 300 AN: 2114

Alfa AF: 0.123 Hom.: 2462

Bravo AF: 0.136

TwinsUK AF: 0.112 AC: 417

ALSPAC AF: 0.117 AC: 452

ESP6500AA AF: 0.200 AC: 880

ESP6500EA AF: 0.117 AC: 1005

ExAC AF: 0.120 AC: 14531

Asia WGS AF: 0.138 AC: 478 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.33
DANN	Benign	0.70
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0015	T
PhyloP100		-1.8
Sift4G	Uncertain	0.015	D
Vest4		0.14
GERP RS		-6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2492367; hg19: chr1-231906589; COSMIC: COSV99697255;