2-227991150-G-C

Variant names:

• chr2-227991150-G-C
• rs16824283
• NM_001142644.2:c.4809C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001142644.2(SPHKAP):​c.4809C>G​(p.Ser1603Arg) 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 1,613,886 control chromosomes in the GnomAD database, including 53,582 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3705 hom., cov: 32)
  • Exomes 𝑓: 0.26 (49877 hom.)
• Consequence: SPHKAP NM_001142644.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0850
• Publications: 22 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060194135).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142644.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPHKAP	NM_001142644.2	MANE Select	c.4809C>G	p.Ser1603Arg	missense	Exon 11 of 12	NP_001136116.1
	SPHKAP	NM_030623.4		c.4722C>G	p.Ser1574Arg	missense	Exon 10 of 11	NP_085126.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPHKAP	ENST00000392056.8	TSL:1 MANE Select	c.4809C>G	p.Ser1603Arg	missense	Exon 11 of 12	ENSP00000375909.3
	SPHKAP	ENST00000344657.5	TSL:1	c.4722C>G	p.Ser1574Arg	missense	Exon 10 of 11	ENSP00000339886.5
	SPHKAP	ENST00000490603.1	TSL:4	n.302C>G		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30491 AN: 152002 Hom.: 3711 Cov.: 32

Gnomad AFR AF: 0.0614

Gnomad AMI AF: 0.108

Gnomad AMR AF: 0.202

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.233

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.279

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.273

Gnomad OTH AF: 0.214

GnomAD2 exomes AF: 0.225 AC: 56379 AN: 250726 AF XY: 0.229

Gnomad AFR exome AF: 0.0578

Gnomad AMR exome AF: 0.159

Gnomad ASJ exome AF: 0.216

Gnomad EAS exome AF: 0.233

Gnomad FIN exome AF: 0.272

Gnomad NFE exome AF: 0.271

Gnomad OTH exome AF: 0.251

GnomAD4 exome AF: 0.256 AC: 374860 AN: 1461766 Hom.: 49877 Cov.: 36 AF XY: 0.255 AC XY: 185717 AN XY: 727180

African (AFR) AF: 0.0558 AC: 1867 AN: 33480

American (AMR) AF: 0.166 AC: 7417 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 5605 AN: 26136

East Asian (EAS) AF: 0.227 AC: 9005 AN: 39674

South Asian (SAS) AF: 0.178 AC: 15318 AN: 86256

European-Finnish (FIN) AF: 0.272 AC: 14514 AN: 53396

Middle Eastern (MID) AF: 0.240 AC: 1385 AN: 5768

European-Non Finnish (NFE) AF: 0.274 AC: 305034 AN: 1111952

Other (OTH) AF: 0.244 AC: 14715 AN: 60390

GnomAD4 genome AF: 0.200 AC: 30478 AN: 152120 Hom.: 3705 Cov.: 32 AF XY: 0.201 AC XY: 14954 AN XY: 74358

African (AFR) AF: 0.0612 AC: 2542 AN: 41520

American (AMR) AF: 0.201 AC: 3080 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 685 AN: 3472

East Asian (EAS) AF: 0.233 AC: 1202 AN: 5154

South Asian (SAS) AF: 0.180 AC: 869 AN: 4820

European-Finnish (FIN) AF: 0.279 AC: 2956 AN: 10586

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.273 AC: 18529 AN: 67972

Other (OTH) AF: 0.210 AC: 442 AN: 2106

Alfa AF: 0.256 Hom.: 3944

Bravo AF: 0.193

TwinsUK AF: 0.275 AC: 1018

ALSPAC AF: 0.274 AC: 1055

ESP6500AA AF: 0.0672 AC: 296

ESP6500EA AF: 0.270 AC: 2318

ExAC AF: 0.222 AC: 27003

Asia WGS AF: 0.169 AC: 588 AN: 3478

EpiCase AF: 0.273

EpiControl AF: 0.273

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.045	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	M
PhyloP100		0.085
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.14
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.031	D
Polyphen		0.97	D
Vest4		0.084
MutPred		0.067		Loss of glycosylation at S1603 (P = 0.0296)
MPC		0.28
ClinPred		0.046	T
GERP RS		-2.2
Varity_R		0.34
gMVP		0.35
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs16824283; hg19: chr2-228855866; COSMIC: COSV60872310;