2-218401662-G-A

Position:

• chr2-218401662-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.018 (54 hom., cov: 33)
  • Exomes 𝑓: 0.0046 (81 hom.)
• Consequence: CTDSP1 NM_021198.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.10

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 54 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTDSP1	NM_021198.3	c.166G>A	p.Ala56Thr	missense_variant	2/7	ENST00000273062.7	NP_067021.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTDSP1	ENST00000273062.7	c.166G>A	p.Ala56Thr	missense_variant	2/7	1	NM_021198.3	ENSP00000273062	P3

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2703 AN: 152180 Hom.: 53 Cov.: 33

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

GnomAD3 exomes AF: 0.00875 AC: 2154 AN: 246078 Hom.: 27 AF XY: 0.00801 AC XY: 1068 AN XY: 133288

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 SAS exome AF: 0.0126

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.: 81 Cov.: 32 AF XY: 0.00472 AC XY: 3418 AN XY: 724876

Gnomad4 AFR exome AF: 0.0488

Gnomad4 AMR exome AF: 0.0103

Gnomad4 ASJ exome AF: 0.0202

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0122

Gnomad4 FIN exome AF: 0.00215

Gnomad4 NFE exome AF: 0.00190

Gnomad4 OTH exome AF: 0.0104

GnomAD4 genome AF: 0.0178 AC: 2710 AN: 152298 Hom.: 54 Cov.: 33 AF XY: 0.0178 AC XY: 1322 AN XY: 74462

Gnomad4 AFR AF: 0.0497

Gnomad4 AMR AF: 0.0169

Gnomad4 ASJ AF: 0.0248

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0104

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00246

Gnomad4 OTH AF: 0.0255

Alfa AF: 0.00689 Hom.: 11

Bravo AF: 0.0197

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.0420 AC: 185

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00902 AC: 1095

Asia WGS AF: 0.0120 AC: 44 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 26, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	8.1
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	.;T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.56	T;T
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.075	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.40	N;N
REVEL	Benign	0.032
Sift	Benign	0.25	T;T
Sift4G	Benign	0.53	T;T
Polyphen		0.0030	.;B
Vest4		0.068
MVP		0.25
MPC		0.050
ClinPred		0.0015	T
GERP RS		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.031
gMVP		0.33

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

Other links and lift over

dbSNP: rs2227249; hg19: chr2-219266385;