2-227991116-G-C

Position:

• chr2-227991116-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001142644.2(SPHKAP):​c.4843C>G​(p.Leu1615Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPHKAP NM_001142644.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.30

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPHKAP	NM_001142644.2	c.4843C>G	p.Leu1615Val	missense_variant	11/12	ENST00000392056.8	NP_001136116.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPHKAP	ENST00000392056.8	c.4843C>G	p.Leu1615Val	missense_variant	11/12	1	NM_001142644.2	ENSP00000375909.3
SPHKAP	ENST00000344657.5	c.4756C>G	p.Leu1586Val	missense_variant	10/11	1		ENSP00000339886.5
SPHKAP	ENST00000490603.1	n.336C>G		non_coding_transcript_exon_variant	4/4	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2024

The c.4843C>G (p.L1615V) alteration is located in exon 11 (coding exon 11) of the SPHKAP gene. This alteration results from a C to G substitution at nucleotide position 4843, causing the leucine (L) at amino acid position 1615 to be replaced by a valine (V). 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	0.10
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.050	T;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.20
Sift	Benign	0.035	D;D
Sift4G	Uncertain	0.025	D;D
Polyphen		1.0	D;D
Vest4		0.34
MutPred		0.69		Loss of stability (P = 0.1789);.;
MVP		0.49
MPC		0.33
ClinPred		0.92	D
GERP RS		5.3
Varity_R		0.50
gMVP		0.39

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: rs764818556; hg19: chr2-228855832;