chr10-51698307-A-G

Variant names:

• chr10-51698307-A-G
• NM_015235.3:c.1243T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015235.3(CSTF2T):​c.1243T>C​(p.Ser415Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CSTF2T NM_015235.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.131
• Publications: 0 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: 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 (MetaRNN=0.0104979575).

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.1243T>C	p.Ser415Pro	missense	Exon 1 of 1	NP_056050.1	Q9H0L4
	PRKG1	NM_006258.4	MANE Select	c.593-106278A>G		intron	N/A	NP_006249.1	Q13976-2
	PRKG1	NM_001098512.3		c.548-106278A>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.1243T>C	p.Ser415Pro	missense	Exon 1 of 1	ENSP00000332444.4	Q9H0L4
	PRKG1	ENST00000373980.11	TSL:1 MANE Select	c.593-106278A>G		intron	N/A	ENSP00000363092.5	Q13976-2
	PRKG1	ENST00000401604.8	TSL:5	c.548-106278A>G		intron	N/A	ENSP00000384200.4	Q13976-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.90
DANN	Benign	0.66
DEOGEN2	Benign	0.034	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.66	N
PhyloP100		0.13
PrimateAI	Benign	0.41	T
PROVEAN	Benign	2.7	N
REVEL	Benign	0.039
Sift	Benign	0.72	T
Sift4G	Benign	1.0	T
Polyphen		0.0040	B
Vest4		0.062
MutPred		0.14		Loss of phosphorylation at S415 (P = 0.002)
MVP		0.15
MPC		0.29
ClinPred		0.13	T
GERP RS		1.5
Varity_R		0.071
gMVP		0.12
Mutation Taster		=81/19	polymorphism

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

hg19: chr10-53458067;