Genetic Variant CTDSP1:p.Ala56Thr (chr2-218401662-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021198.3(CTDSP1):c.166G>A(p.Ala56Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00583 in 1,609,526 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A56V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.018 ( 54 hom., cov: 33)

Exomes 𝑓: 0.0046 ( 81 hom. )

Consequence

CTDSP1
NM_021198.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.10

Publications

8 publications found

Variant links:

Genes affected

CTDSP1 (HGNC:21614): (CTD small phosphatase 1) This gene encodes a member of the small C-terminal domain phosphatase (SCP) family of nuclear phosphatases. These proteins play a role in transcriptional regulation through specific dephosphorylation of phosphoserine 5 within tandem heptapeptide repeats of the C-terminal domain of RNA polymerase II. The encoded protein plays a role in neuronal gene silencing in non-neuronal cells, and may also inhibit osteoblast differentiation. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Oct 2011]

CTDSP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018684566).

BP6

Variant 2-218401662-G-A is Benign according to our data. Variant chr2-218401662-G-A is described in ClinVar as Benign. ClinVar VariationId is 769265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0178 (2710/152298) while in subpopulation AFR AF = 0.0497 (2066/41556). AF 95% confidence interval is 0.0479. There are 54 homozygotes in GnomAd4. There are 1322 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 54 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021198.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CTDSP1	NM_021198.3	MANE Select	c.166G>A	p.Ala56Thr	missense	Exon 2 of 7	NP_067021.1	Q9GZU7-1
CTDSP1	NM_001400269.1		c.166G>A	p.Ala56Thr	missense	Exon 2 of 6	NP_001387198.1
CTDSP1	NM_001400270.1		c.166G>A	p.Ala56Thr	missense	Exon 2 of 6	NP_001387199.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CTDSP1	ENST00000273062.7	TSL:1 MANE Select	c.166G>A	p.Ala56Thr	missense	Exon 2 of 7	ENSP00000273062.2	Q9GZU7-1
CTDSP1	ENST00000885505.1		c.166G>A	p.Ala56Thr	missense	Exon 2 of 7	ENSP00000555564.1
CTDSP1	ENST00000452977.6	TSL:5	c.166G>A	p.Ala56Thr	missense	Exon 2 of 7	ENSP00000404301.2	H7C270

Frequencies

GnomAD3 genomes

AF:

0.0178

AC:

2703

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0496

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0169

Gnomad ASJ

AF:

0.0248

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0106

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.00245

Gnomad OTH

AF:

0.0263

GnomAD2 exomes

AF:

0.00875

AC:

2154

AN:

246078

AF XY:

0.00801

show subpopulations

Gnomad AFR exome

AF:

0.0492

Gnomad AMR exome

AF:

0.0106

Gnomad ASJ exome

AF:

0.0202

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00220

Gnomad NFE exome

AF:

0.00283

Gnomad OTH exome

AF:

0.0117

GnomAD4 exome

AF:

0.00458

AC:

6679

AN:

1457228

Hom.:

Cov.:

AF XY:

0.00472

AC XY:

3418

AN XY:

724876

show subpopulations

African (AFR)

AF:

0.0488

AC:

1627

AN:

33318

American (AMR)

AF:

0.0103

AC:

452

AN:

43928

Ashkenazi Jewish (ASJ)

AF:

0.0202

AC:

521

AN:

25814

East Asian (EAS)

AF:

0.00

AC:

AN:

39642

South Asian (SAS)

AF:

0.0122

AC:

1044

AN:

85794

European-Finnish (FIN)

AF:

0.00215

AC:

114

AN:

53030

Middle Eastern (MID)

AF:

0.0334

AC:

192

AN:

5744

European-Non Finnish (NFE)

AF:

0.00190

AC:

2105

AN:

1109762

Other (OTH)

AF:

0.0104

AC:

624

AN:

60196

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

318

637

955

1274

1592

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

272

408

544

680

<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

AF:

0.0178

AC:

2710

AN:

152298

Hom.:

Cov.:

AF XY:

0.0178

AC XY:

1322

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0497

AC:

2066

AN:

41556

American (AMR)

AF:

0.0169

AC:

258

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0248

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.0104

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00246

AC:

167

AN:

68018

Other (OTH)

AF:

0.0255

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

128

256

385

513

641

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00728

Hom.:

Bravo

AF:

0.0197

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.0420

AC:

185

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.00902

AC:

1095

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.60

CADD

Benign

8.1

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.011

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.56

MetaRNN

Benign

0.0019

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.075

PhyloP100

1.1

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.40

REVEL

Benign

0.032

Sift

Benign

0.25

Sift4G

Benign

0.53

Polyphen

0.0030

Vest4

0.068

MVP

0.25

MPC

0.050

ClinPred

0.0015

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.031

gMVP

0.33

Mutation Taster

=97/3

polymorphism

(source)

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

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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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over