Variant chr2-227991280-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001142644.2(SPHKAP):c.4768A>C(p.Thr1590Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

SPHKAP
NM_001142644.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.425

Variant links:

Genes affected

SPHKAP (HGNC:30619): (SPHK1 interactor, AKAP domain containing) Enables protein kinase A binding activity. Predicted to be located in Z disc. Predicted to be active in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

SPHKAP links:

LOC105373918 (HGNC:):

LOC105373918 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.052393734).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPHKAP	NM_001142644.2 link	c.4768A>C	p.Thr1590Pro	missense_variant	10/12	ENST00000392056.8	NP_001136116.1	Q2M3C7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SPHKAP	ENST00000392056.8 link	c.4768A>C	p.Thr1590Pro	missense_variant	10/12	1	NM_001142644.2	ENSP00000375909.3	Q2M3C7-1
SPHKAP	ENST00000344657.5 link	c.4681A>C	p.Thr1561Pro	missense_variant	9/11	1		ENSP00000339886.5	Q2M3C7-2
SPHKAP	ENST00000490603.1 link	n.261A>C		non_coding_transcript_exon_variant	3/4	4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251082

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135678

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000274

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 05, 2024

The c.4768A>C (p.T1590P) alteration is located in exon 10 (coding exon 10) of the SPHKAP gene. This alteration results from a A to C substitution at nucleotide position 4768, causing the threonine (T) at amino acid position 1590 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.74

CADD

Benign

4.3

DANN

Benign

0.94

DEOGEN2

Benign

0.015

T;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.18

T;T

M_CAP

Benign

0.0074

MetaRNN

Benign

0.052

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

L;.

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.10

Sift

Benign

0.20

T;T

Sift4G

Benign

0.13

T;T

Polyphen

0.82

P;P

Vest4

0.18

MutPred

0.12

Loss of phosphorylation at T1590 (P = 0.0197);.;

MVP

0.048

MPC

0.059

ClinPred

0.21

GERP RS

-2.5

Varity_R

0.16

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over