9-83806370-T-A

Position:

• chr9-83806370-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025211.4(GKAP1):​c.148A>T​(p.Thr50Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000351 in 1,425,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: GKAP1 NM_025211.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.32

Genes affected

GKAP1 (HGNC:17496): (G kinase anchoring protein 1) This gene encodes a protein that is highly similar to the mouse cGMP-dependent protein kinase anchoring protein 42kDa. The mouse protein has been found to localize with the Golgi and recruit cGMP-dependent protein kinase I alpha to the Golgi in mouse testes. It is thought to play a role in germ cell development. Transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0921098).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GKAP1	NM_025211.4	c.148A>T	p.Thr50Ser	missense_variant	3/13	ENST00000376371.7	NP_079487.2
GKAP1	NM_001135953.2	c.148A>T	p.Thr50Ser	missense_variant	3/12		NP_001129425.1
GKAP1	XM_005252241.3	c.148A>T	p.Thr50Ser	missense_variant	3/13		XP_005252298.1
GKAP1	XM_011519058.3	c.148A>T	p.Thr50Ser	missense_variant	4/14		XP_011517360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GKAP1	ENST00000376371.7	c.148A>T	p.Thr50Ser	missense_variant	3/13	1	NM_025211.4	ENSP00000365550.2
GKAP1	ENST00000376365.7	c.148A>T	p.Thr50Ser	missense_variant	3/12	1		ENSP00000365544.3
GKAP1	ENST00000485742.5	c.148A>T	p.Thr50Ser	missense_variant	3/3	3		ENSP00000417621.1
GKAP1	ENST00000388782.8	n.148A>T		non_coding_transcript_exon_variant	5/11	2		ENSP00000373434.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000351 AC: 5 AN: 1425948 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 706314

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000458

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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 17, 2023

The c.148A>T (p.T50S) alteration is located in exon 3 (coding exon 1) of the GKAP1 gene. This alteration results from a A to T substitution at nucleotide position 148, causing the threonine (T) at amino acid position 50 to be replaced by a serine (S). 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	0.076
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Benign	0.71
DEOGEN2	Benign	0.013	T;.;T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.70	T;T;T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.092	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.17	N;N;N
REVEL	Benign	0.073
Sift	Benign	0.38	T;T;T
Sift4G	Benign	0.98	T;T;.
Polyphen		0.0	B;B;.
Vest4		0.058
MutPred		0.16		Loss of glycosylation at S49 (P = 0.12);Loss of glycosylation at S49 (P = 0.12);Loss of glycosylation at S49 (P = 0.12);
MVP		0.12
MPC		0.059
ClinPred		0.067	T
GERP RS		2.7
Varity_R		0.038
gMVP		0.055

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: rs779809540; hg19: chr9-86421285;