1-231694266-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_018662.3(DISC1):c.508C>T(p.Arg170Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000416 in 1,614,250 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (5 hom.)
• Consequence: DISC1 NM_018662.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.200

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:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037977397).
• BP6: Variant 1-231694266-C-T is Benign according to our data. Variant chr1-231694266-C-T is described in ClinVar as [Benign]. Clinvar id is 783018.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DISC1	NM_018662.3	c.508C>T	p.Arg170Cys	missense_variant	2/13	ENST00000439617.8
TSNAX-DISC1	NR_028393.1	n.1229C>T		non_coding_transcript_exon_variant	6/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DISC1	ENST00000439617.8	c.508C>T	p.Arg170Cys	missense_variant	2/13	5	NM_018662.3	A2

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152262 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

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: 0.0000441

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00190 AC: 472 AN: 248748 Hom.: 4 AF XY: 0.00126 AC XY: 170 AN XY: 134706

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0131

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000270

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000410 AC: 600 AN: 1461870 Hom.: 5 Cov.: 32 AF XY: 0.000329 AC XY: 239 AN XY: 727232

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.0121

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152380 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74524

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000159 Hom.: 1

Bravo AF: 0.00116

ExAC AF: 0.00129 AC: 157

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

DISC1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 16, 2022

This variant is classified as 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	0.12
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	17
Dann	Uncertain	0.99
Eigen	Benign	-0.90
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.026	N
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0038	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	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	0.26	T
PROVEAN	Uncertain	-3.8	D;N;.;N;N;N;.;N;N;.;.;N;.
REVEL	Benign	0.13
Sift	Uncertain	0.027	D;D;.;.;D;D;.;D;D;.;.;D;.
Sift4G	Benign	0.062	T;T;T;D;T;T;T;T;T;T;T;T;.
Polyphen		0.82	P;.;.;.;D;D;.;.;D;.;.;D;.
Vest4		0.18
MVP		0.34
MPC		0.46
ClinPred		0.047	T
GERP RS		0.067
Varity_R		0.055
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs186593988; hg19: chr1-231830012;