19-49873106-C-G

Variant names:

• chr19-49873106-C-G
• rs755915845
• NM_001098633.4:c.190G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001098633.4(AKT1S1):​c.190G>C​(p.Asp64His) variant causes a missense change. The variant allele was found at a frequency of 0.000000717 in 1,394,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D64N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: AKT1S1 NM_001098633.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.64
• Publications: 0 publications found

Genes affected

AKT1S1 (HGNC:28426): (AKT1 substrate 1) AKT1S1 is a proline-rich substrate of AKT (MIM 164730) that binds 14-3-3 protein (see YWHAH, MIM 113508) when phosphorylated (Kovacina et al., 2003 [PubMed 12524439]).[supplied by OMIM, Mar 2008]

PNKP (HGNC:9154): (polynucleotide kinase 3'-phosphatase) This locus represents a gene involved in DNA repair. In response to ionizing radiation or oxidative damage, the protein encoded by this locus catalyzes 5' phosphorylation and 3' dephosphorylation of nucleic acids. Mutations at this locus have been associated with microcephaly, seizures, and developmental delay.[provided by RefSeq, Sep 2010]

PNKP Gene-Disease associations (from GenCC):

• ataxia - oculomotor apraxia type 4

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, G2P, Orphanet
• microcephaly, seizures, and developmental delay

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• Charcot-Marie-Tooth disease type 2B2

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.795

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098633.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT1S1	NM_001098633.4	MANE Select	c.190G>C	p.Asp64His	missense	Exon 2 of 5	NP_001092103.1	Q96B36-1
	AKT1S1	NM_032375.5		c.250G>C	p.Asp84His	missense	Exon 2 of 5	NP_115751.3	Q96B36-3
	AKT1S1	NM_001098632.2		c.190G>C	p.Asp64His	missense	Exon 2 of 5	NP_001092102.1	Q96B36-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKT1S1	ENST00000344175.10	TSL:3 MANE Select	c.190G>C	p.Asp64His	missense	Exon 2 of 5	ENSP00000341698.5	Q96B36-1
	AKT1S1	ENST00000391835.1	TSL:1	c.250G>C	p.Asp84His	missense	Exon 2 of 5	ENSP00000375711.1	Q96B36-3
	AKT1S1	ENST00000391832.7	TSL:1	c.190G>C	p.Asp64His	missense	Exon 2 of 5	ENSP00000375708.3	Q96B36-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1394706 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 688720

African (AFR) AF: 0.00 AC: 0 AN: 31872

American (AMR) AF: 0.00 AC: 0 AN: 36194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25124

East Asian (EAS) AF: 0.00 AC: 0 AN: 36142

South Asian (SAS) AF: 0.00 AC: 0 AN: 79542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41192

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5146

European-Non Finnish (NFE) AF: 9.25e-7 AC: 1 AN: 1081464

Other (OTH) AF: 0.00 AC: 0 AN: 58030

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.9	L
PhyloP100		5.6
PrimateAI	Pathogenic	0.96	D
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.020	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.40		Gain of MoRF binding (P = 0.0603)
MVP		0.91
MPC		0.88
ClinPred		0.96	D
GERP RS		4.9
Varity_R		0.61
gMVP		0.84
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs755915845; hg19: chr19-50376363;