chr1-231693954-C-T

Position:

chr1-231693954-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_018662.3(DISC1):c.196C>T(p.Arg66Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000524 in 1,614,094 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0026 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00031 ( 3 hom. )

Consequence

DISC1
NM_018662.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.713

Variant links:

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]

DISC1 links:

TSNAX-DISC1 (HGNC:):

TSNAX-DISC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036754906).

BP6

Variant 1-231693954-C-T is Benign according to our data. Variant chr1-231693954-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 785956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DISC1	NM_018662.3 linkuse as main transcript	c.196C>T	p.Arg66Trp	missense_variant	2/13	ENST00000439617.8	NP_061132.2
TSNAX-DISC1	NR_028393.1 linkuse as main transcript	n.917C>T		non_coding_transcript_exon_variant	6/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DISC1	ENST00000439617.8 linkuse as main transcript	c.196C>T	p.Arg66Trp	missense_variant	2/13	5	NM_018662.3	ENSP00000403888	A2	Q9NRI5-1

Frequencies

GnomAD3 genomes

AF:

0.00256

AC:

389

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00902

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000677

AC:

168

AN:

248234

Hom.:

AF XY:

0.000550

AC XY:

AN XY:

134460

show subpopulations

Gnomad AFR exome

AF:

0.00909

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000436

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000631

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000311

AC:

455

AN:

1461776

Hom.:

Cov.:

AF XY:

0.000275

AC XY:

200

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.00920

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000674

Gnomad4 OTH exome

AF:

0.000629

GnomAD4 genome

AF:

0.00256

AC:

390

AN:

152318

Hom.:

Cov.:

AF XY:

0.00247

AC XY:

184

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00902

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000607

Hom.:

Bravo

AF:

0.00269

ESP6500AA

AF:

0.00885

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000832

AC:

101

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 16, 2018	- -

DISC1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 24, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.60

CADD

Benign

4.2

DANN

Benign

0.94

DEOGEN2

Benign

0.031

.;.;.;.;.;.;.;.;.;T;.;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.017

LIST_S2

Uncertain

0.88

D;D;D;D;D;D;D;D;D;D;D;D;D

MetaRNN

Benign

0.0037

T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.60

N;N;N;N;.;N;N;N;N;.;.;N;N

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.23

PROVEAN

Uncertain

-2.6

D;N;.;N;N;N;.;N;N;.;.;N;.

REVEL

Benign

0.049

Sift

Benign

0.044

D;T;.;.;T;T;.;T;T;.;.;T;.

Sift4G

Benign

0.17

T;T;T;D;T;T;T;T;T;T;T;T;.

Polyphen

0.012

B;.;.;.;B;B;.;.;B;.;.;B;.

Vest4

0.12

MVP

0.23

MPC

0.12

ClinPred

0.0086

GERP RS

-4.8

Varity_R

0.079

gMVP

0.15

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over