dbSNP rs821617: DISC1:c.*250A>C (chr1-232009141-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001164538.2(DISC1):c.2399A>C(p.Lys800Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000421 in 1,425,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 4/4 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

DISC1
NM_001164538.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.351

Publications

17 publications found

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: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]

TSNAX-DISC1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164538.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DISC1	NM_018662.3	MANE Select	c.2307+92A>C		intron	N/A	NP_061132.2	Q9NRI5-1
DISC1	NM_001164538.2		c.2399A>C	p.Lys800Thr	missense	Exon 11 of 11	NP_001158010.1	C4P098
DISC1	NM_001164541.2		c.*250A>C		3_prime_UTR	Exon 10 of 10	NP_001158013.1	Q9NRI5-8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DISC1	ENST00000535983.5	TSL:1	c.*250A>C	3_prime_UTR	Exon 10 of 10	ENSP00000443996.1	Q9NRI5-8
DISC1	ENST00000439617.8	TSL:5 MANE Select	c.2307+92A>C	intron	N/A	ENSP00000403888.4	Q9NRI5-1
DISC1	ENST00000366637.8	TSL:5	c.2241+158A>C	intron	N/A	ENSP00000355597.6	Q9NRI5-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000489

AC:

AN:

204542

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000349

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000421

AC:

AN:

1425024

Hom.:

Cov.:

AF XY:

0.00000426

AC XY:

AN XY:

704446

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32840

American (AMR)

AF:

0.0000250

AC:

AN:

40020

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25280

East Asian (EAS)

AF:

0.00

AC:

AN:

38844

South Asian (SAS)

AF:

0.00

AC:

AN:

80812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51724

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5538

European-Non Finnish (NFE)

AF:

0.00000458

AC:

AN:

1091058

Other (OTH)

AF:

0.00

AC:

AN:

58908

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

5.4

(source)

DANN

Benign

0.44

PhyloP100

-0.35

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over