19-49869930-T-C

Variant names:

• chr19-49869930-T-C
• NM_001098633.4:c.758A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_001098633.4(AKT1S1):​c.758A>G​(p.Lys253Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000364 in 1,373,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: AKT1S1 NM_001098633.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.44
• 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: Orphanet, G2P, Laboratory for Molecular Medicine
• microcephaly, seizures, and developmental delay

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14947116).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT1S1	NM_001098633.4	c.758A>G	p.Lys253Arg	missense_variant	Exon 5 of 5	ENST00000344175.10	NP_001092103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT1S1	ENST00000344175.10	c.758A>G	p.Lys253Arg	missense_variant	Exon 5 of 5	3	NM_001098633.4	ENSP00000341698.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000364 AC: 5 AN: 1373180 Hom.: 0 Cov.: 30 AF XY: 0.00000148 AC XY: 1 AN XY: 673948

African (AFR) AF: 0.00 AC: 0 AN: 29908

American (AMR) AF: 0.00 AC: 0 AN: 35814

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24368

East Asian (EAS) AF: 0.00 AC: 0 AN: 33662

South Asian (SAS) AF: 0.00 AC: 0 AN: 77794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5580

European-Non Finnish (NFE) AF: 0.00000472 AC: 5 AN: 1060328

Other (OTH) AF: 0.00 AC: 0 AN: 56484

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 27, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.758A>G (p.K253R) alteration is located in exon 5 (coding exon 4) of the AKT1S1 gene. This alteration results from a A to G substitution at nucleotide position 758, causing the lysine (K) at amino acid position 253 to be replaced by an arginine (R). 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	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	19
DANN	Benign	0.87
DEOGEN2	Benign	0.12	T;T;T;T;T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.75	T;.;.;.;.;T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.15	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;N;N;N;.
PhyloP100		2.4
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.72	N;N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.63	T;T;T;T;T;T
Sift4G	Benign	0.83	T;T;T;T;T;T
Polyphen		0.98	D;D;D;D;D;.
Vest4		0.13
MutPred		0.20		Loss of methylation at K253 (P = 0.0187);Loss of methylation at K253 (P = 0.0187);Loss of methylation at K253 (P = 0.0187);Loss of methylation at K253 (P = 0.0187);Loss of methylation at K253 (P = 0.0187);.;
MVP		0.68
MPC		1.6
ClinPred		0.37	T
GERP RS		2.6
Varity_R		0.16
gMVP		0.10
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

hg19: chr19-50373187;