2-228018254-T-C

Position:

• chr2-228018254-T-C

Variant summary

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

The NM_001142644.2(SPHKAP):​c.2600A>G​(p.Gln867Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,613,986 control chromosomes in the GnomAD database, including 26,248 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.21 (3651 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22597 hom.)
• Consequence: SPHKAP NM_001142644.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.743

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=4.5624375E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.374 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPHKAP	NM_001142644.2	c.2600A>G	p.Gln867Arg	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.2600A>G	p.Gln867Arg	missense_variant	7/12	1	NM_001142644.2	ENSP00000375909.3
SPHKAP	ENST00000344657.5	c.2600A>G	p.Gln867Arg	missense_variant	7/11	1		ENSP00000339886.5

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31425 AN: 152012 Hom.: 3641 Cov.: 32

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.0989

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.388

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.188

GnomAD3 exomes AF: 0.194 AC: 48748 AN: 251372 Hom.: 5724 AF XY: 0.184 AC XY: 25001 AN XY: 135850

Gnomad AFR exome AF: 0.290

Gnomad AMR exome AF: 0.253

Gnomad ASJ exome AF: 0.134

Gnomad EAS exome AF: 0.410

Gnomad SAS exome AF: 0.103

Gnomad FIN exome AF: 0.207

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.167

GnomAD4 exome AF: 0.168 AC: 245818 AN: 1461856 Hom.: 22597 Cov.: 36 AF XY: 0.165 AC XY: 120339 AN XY: 727230

Gnomad4 AFR exome AF: 0.284

Gnomad4 AMR exome AF: 0.250

Gnomad4 ASJ exome AF: 0.134

Gnomad4 EAS exome AF: 0.354

Gnomad4 SAS exome AF: 0.105

Gnomad4 FIN exome AF: 0.205

Gnomad4 NFE exome AF: 0.158

Gnomad4 OTH exome AF: 0.181

GnomAD4 genome AF: 0.207 AC: 31464 AN: 152130 Hom.: 3651 Cov.: 32 AF XY: 0.205 AC XY: 15267 AN XY: 74368

Gnomad4 AFR AF: 0.286

Gnomad4 AMR AF: 0.211

Gnomad4 ASJ AF: 0.135

Gnomad4 EAS AF: 0.388

Gnomad4 SAS AF: 0.105

Gnomad4 FIN AF: 0.198

Gnomad4 NFE AF: 0.158

Gnomad4 OTH AF: 0.188

Alfa AF: 0.164 Hom.: 3979

Bravo AF: 0.214

TwinsUK AF: 0.169 AC: 625

ALSPAC AF: 0.156 AC: 601

ESP6500AA AF: 0.291 AC: 1280

ESP6500EA AF: 0.159 AC: 1370

ExAC AF: 0.192 AC: 23328

Asia WGS AF: 0.241 AC: 839 AN: 3478

EpiCase AF: 0.157

EpiControl AF: 0.150

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.4
DANN	Benign	0.78
DEOGEN2	Benign	0.0088	T;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.38	T;T
MetaRNN	Benign	0.00046	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.35	N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.50	N;N
REVEL	Benign	0.058
Sift	Benign	0.28	T;T
Sift4G	Benign	0.42	T;T
Polyphen		0.0	B;B
Vest4		0.012
MPC		0.050
ClinPred		0.0048	T
GERP RS		-0.75
Varity_R		0.050
gMVP		0.12

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: rs3828161; hg19: chr2-228882970; COSMIC: COSV60880175;