10-51699238-A-G

Variant names:

• chr10-51699238-A-G
• rs2292828
• NM_015235.3:c.312T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_015235.3(CSTF2T):​c.312T>C​(p.Leu104Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,613,698 control chromosomes in the GnomAD database, including 31,158 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.27 (8388 hom., cov: 31)
  • Exomes 𝑓: 0.16 (22770 hom.)
• Consequence: CSTF2T NM_015235.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.15
• Publications: 14 publications found

Genes affected

CSTF2T (HGNC:17086): (cleavage stimulation factor subunit 2 tau variant) Enables RNA binding activity. Predicted to be involved in pre-mRNA cleavage required for polyadenylation. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

PRKG1 (HGNC:9414): (protein kinase cGMP-dependent 1) Mammals have three different isoforms of cyclic GMP-dependent protein kinase (Ialpha, Ibeta, and II). These PRKG isoforms act as key mediators of the nitric oxide/cGMP signaling pathway and are important components of many signal transduction processes in diverse cell types. This PRKG1 gene on human chromosome 10 encodes the soluble Ialpha and Ibeta isoforms of PRKG by alternative transcript splicing. A separate gene on human chromosome 4, PRKG2, encodes the membrane-bound PRKG isoform II. The PRKG1 proteins play a central role in regulating cardiovascular and neuronal functions in addition to relaxing smooth muscle tone, preventing platelet aggregation, and modulating cell growth. This gene is most strongly expressed in all types of smooth muscle, platelets, cerebellar Purkinje cells, hippocampal neurons, and the lateral amygdala. Isoforms Ialpha and Ibeta have identical cGMP-binding and catalytic domains but differ in their leucine/isoleucine zipper and autoinhibitory sequences and therefore differ in their dimerization substrates and kinase enzyme activity. [provided by RefSeq, Sep 2011]

PRKG1 Gene-Disease associations (from GenCC):

• aortic aneurysm, familial thoracic 8

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD, Unknown Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP7: Synonymous conserved (PhyloP=-3.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.574 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015235.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSTF2T	NM_015235.3	MANE Select	c.312T>C	p.Leu104Leu	synonymous	Exon 1 of 1	NP_056050.1	Q9H0L4
	PRKG1	NM_006258.4	MANE Select	c.593-105347A>G		intron	N/A	NP_006249.1	Q13976-2
	PRKG1	NM_001098512.3		c.548-105347A>G		intron	N/A	NP_001091982.1	Q13976-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSTF2T	ENST00000331173.6	TSL:6 MANE Select	c.312T>C	p.Leu104Leu	synonymous	Exon 1 of 1	ENSP00000332444.4	Q9H0L4
	PRKG1	ENST00000373980.11	TSL:1 MANE Select	c.593-105347A>G		intron	N/A	ENSP00000363092.5	Q13976-2
	PRKG1	ENST00000401604.8	TSL:5	c.548-105347A>G		intron	N/A	ENSP00000384200.4	Q13976-1

Frequencies

GnomAD3 genomes AF: 0.270 AC: 41001 AN: 151698 Hom.: 8350 Cov.: 31

Gnomad AFR AF: 0.580

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.203

Gnomad SAS AF: 0.205

Gnomad FIN AF: 0.207

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.235

GnomAD2 exomes AF: 0.183 AC: 45987 AN: 251214 AF XY: 0.178

Gnomad AFR exome AF: 0.583

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.171

Gnomad EAS exome AF: 0.187

Gnomad FIN exome AF: 0.193

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.168

GnomAD4 exome AF: 0.159 AC: 232571 AN: 1461882 Hom.: 22770 Cov.: 34 AF XY: 0.159 AC XY: 115863 AN XY: 727246

African (AFR) AF: 0.595 AC: 19928 AN: 33480

American (AMR) AF: 0.111 AC: 4975 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 4430 AN: 26136

East Asian (EAS) AF: 0.241 AC: 9584 AN: 39700

South Asian (SAS) AF: 0.211 AC: 18209 AN: 86258

European-Finnish (FIN) AF: 0.192 AC: 10260 AN: 53414

Middle Eastern (MID) AF: 0.184 AC: 1063 AN: 5768

European-Non Finnish (NFE) AF: 0.138 AC: 153383 AN: 1112006

Other (OTH) AF: 0.178 AC: 10739 AN: 60396

GnomAD4 genome AF: 0.271 AC: 41100 AN: 151816 Hom.: 8388 Cov.: 31 AF XY: 0.269 AC XY: 19983 AN XY: 74194

African (AFR) AF: 0.581 AC: 24011 AN: 41360

American (AMR) AF: 0.144 AC: 2199 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 565 AN: 3468

East Asian (EAS) AF: 0.204 AC: 1042 AN: 5114

South Asian (SAS) AF: 0.204 AC: 981 AN: 4808

European-Finnish (FIN) AF: 0.207 AC: 2185 AN: 10548

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.139 AC: 9435 AN: 67930

Other (OTH) AF: 0.234 AC: 493 AN: 2108

Alfa AF: 0.179 Hom.: 3618

Bravo AF: 0.279

Asia WGS AF: 0.234 AC: 815 AN: 3478

EpiCase AF: 0.134

EpiControl AF: 0.136

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.16
DANN	Benign	0.60
PhyloP100		-3.2
PromoterAI		0.036	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2292828; hg19: chr10-53458998; COSMIC: COSV58656080;