Genetic Variant SPHKAP:p.Val1658Leu (chr2-227981848-C-G) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001142644.2(SPHKAP):c.4972G>C(p.Val1658Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00854 in 1,612,962 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0066 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0087 ( 60 hom. )

Consequence

SPHKAP
NM_001142644.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.58

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 Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0047121346).

BP6

Variant 2-227981848-C-G is Benign according to our data. Variant chr2-227981848-C-G is described in ClinVar as [Benign]. Clinvar id is 788963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPHKAP	NM_001142644.2 link	c.4972G>C	p.Val1658Leu	missense_variant	Exon 12 of 12	ENST00000392056.8	NP_001136116.1	Q2M3C7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPHKAP	ENST00000392056.8 link	c.4972G>C	p.Val1658Leu	missense_variant	Exon 12 of 12	1	NM_001142644.2	ENSP00000375909.3		Q2M3C7-1
SPHKAP	ENST00000344657.5 link	c.4885G>C	p.Val1629Leu	missense_variant	Exon 11 of 11	1		ENSP00000339886.5		Q2M3C7-2

Frequencies

GnomAD3 genomes

AF:

0.00657

AC:

999

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00164

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00805

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00982

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00989

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.00811

AC:

2023

AN:

249464

Hom.:

AF XY:

0.00787

AC XY:

1062

AN XY:

134872

show subpopulations

Gnomad AFR exome

AF:

0.00173

Gnomad AMR exome

AF:

0.0118

Gnomad ASJ exome

AF:

0.00440

Gnomad EAS exome

AF:

0.00848

Gnomad SAS exome

AF:

0.00562

Gnomad FIN exome

AF:

0.00200

Gnomad NFE exome

AF:

0.0101

Gnomad OTH exome

AF:

0.00626

GnomAD4 exome

AF:

0.00875

AC:

12777

AN:

1460698

Hom.:

Cov.:

AF XY:

0.00863

AC XY:

6268

AN XY:

726646

show subpopulations

Gnomad4 AFR exome

AF:

0.00186

Gnomad4 AMR exome

AF:

0.0109

Gnomad4 ASJ exome

AF:

0.00414

Gnomad4 EAS exome

AF:

0.00976

Gnomad4 SAS exome

AF:

0.00526

Gnomad4 FIN exome

AF:

0.00242

Gnomad4 NFE exome

AF:

0.00959

Gnomad4 OTH exome

AF:

0.00726

GnomAD4 genome

AF:

0.00655

AC:

998

AN:

152264

Hom.:

Cov.:

AF XY:

0.00681

AC XY:

507

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00164

Gnomad4 AMR

AF:

0.00804

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00984

Gnomad4 SAS

AF:

0.00477

Gnomad4 FIN

AF:

0.00198

Gnomad4 NFE

AF:

0.00990

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.00375

Hom.:

Bravo

AF:

0.00720

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00930

AC:

ExAC

AF:

0.00793

AC:

963

Asia WGS

AF:

0.00693

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 24, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.048

T;.

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.86

D;D

MetaRNN

Benign

0.0047

T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.2

M;.

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.82

N;N

REVEL

Benign

0.081

Sift

Benign

0.14

T;T

Sift4G

Benign

0.29

T;T

Polyphen

1.0

D;B

Vest4

0.45

MutPred

0.39

Loss of MoRF binding (P = 0.0972);.;

MVP

0.14

MPC

0.12

ClinPred

0.020

GERP RS

5.8

Varity_R

0.27

gMVP

0.56

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

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