rs3811515

Positions:

• chr2-228018313-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001142644.2(SPHKAP):​c.2541T>G​(p.His847Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 1,613,900 control chromosomes in the GnomAD database, including 54,530 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.20 (3960 hom., cov: 32)
  • Exomes 𝑓: 0.26 (50570 hom.)
• Consequence: SPHKAP NM_001142644.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.226

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]

LOC105373918 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.0601025E-4).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPHKAP	NM_001142644.2	c.2541T>G	p.His847Gln	missense_variant	7/12	ENST00000392056.8	NP_001136116.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPHKAP	ENST00000392056.8	c.2541T>G	p.His847Gln	missense_variant	7/12	1	NM_001142644.2	ENSP00000375909.3
SPHKAP	ENST00000344657.5	c.2541T>G	p.His847Gln	missense_variant	7/11	1		ENSP00000339886.5

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30667 AN: 151926 Hom.: 3954 Cov.: 32

Gnomad AFR AF: 0.0566

Gnomad AMI AF: 0.488

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.271

Gnomad EAS AF: 0.221

Gnomad SAS AF: 0.428

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.277

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.221

GnomAD3 exomes AF: 0.266 AC: 66825 AN: 251402 Hom.: 10107 AF XY: 0.274 AC XY: 37223 AN XY: 135860

Gnomad AFR exome AF: 0.0525

Gnomad AMR exome AF: 0.335

Gnomad ASJ exome AF: 0.270

Gnomad EAS exome AF: 0.216

Gnomad SAS exome AF: 0.432

Gnomad FIN exome AF: 0.196

Gnomad NFE exome AF: 0.252

Gnomad OTH exome AF: 0.261

GnomAD4 exome AF: 0.256 AC: 373743 AN: 1461854 Hom.: 50570 Cov.: 62 AF XY: 0.261 AC XY: 189917 AN XY: 727232

Gnomad4 AFR exome AF: 0.0464

Gnomad4 AMR exome AF: 0.327

Gnomad4 ASJ exome AF: 0.267

Gnomad4 EAS exome AF: 0.268

Gnomad4 SAS exome AF: 0.424

Gnomad4 FIN exome AF: 0.197

Gnomad4 NFE exome AF: 0.249

Gnomad4 OTH exome AF: 0.239

GnomAD4 genome AF: 0.202 AC: 30677 AN: 152046 Hom.: 3960 Cov.: 32 AF XY: 0.206 AC XY: 15272 AN XY: 74290

Gnomad4 AFR AF: 0.0565

Gnomad4 AMR AF: 0.293

Gnomad4 ASJ AF: 0.271

Gnomad4 EAS AF: 0.222

Gnomad4 SAS AF: 0.429

Gnomad4 FIN AF: 0.192

Gnomad4 NFE AF: 0.246

Gnomad4 OTH AF: 0.221

Alfa AF: 0.245 Hom.: 11682

Bravo AF: 0.199

TwinsUK AF: 0.240 AC: 890

ALSPAC AF: 0.248 AC: 954

ESP6500AA AF: 0.0640 AC: 282

ESP6500EA AF: 0.252 AC: 2167

ExAC AF: 0.264 AC: 32077

Asia WGS AF: 0.335 AC: 1165 AN: 3478

EpiCase AF: 0.247

EpiControl AF: 0.260

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.69
DANN	Benign	0.78
DEOGEN2	Benign	0.014	T;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.41	T;T
MetaRNN	Benign	0.00031	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.7	L;L
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.10
Sift	Benign	0.13	T;T
Sift4G	Benign	0.48	T;T
Polyphen		0.011	B;B
Vest4		0.025
MutPred		0.025		Loss of glycosylation at P846 (P = 0.1735);Loss of glycosylation at P846 (P = 0.1735);
MPC		0.049
ClinPred		0.0034	T
GERP RS		0.98
Varity_R		0.052
gMVP		0.14

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: rs3811515; hg19: chr2-228883029; COSMIC: COSV60870915;