rs373953482

Variant names:

• chr19-49869986-C-A
• rs373953482
• NM_001098633.4:c.702G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-49869986-C-A
• chr19-49869986-C-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001098633.4(AKT1S1):​c.702G>T​(p.Gln234His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,548,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: AKT1S1 NM_001098633.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.00
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22240755).
• BS2: High AC in GnomAd4 at 5 AD gene.

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.702G>T	p.Gln234His	missense	Exon 5 of 5	NP_001092103.1	Q96B36-1
	AKT1S1	NM_032375.5		c.762G>T	p.Gln254His	missense	Exon 5 of 5	NP_115751.3	Q96B36-3
	AKT1S1	NM_001098632.2		c.702G>T	p.Gln234His	missense	Exon 5 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.702G>T	p.Gln234His	missense	Exon 5 of 5	ENSP00000341698.5	Q96B36-1
	AKT1S1	ENST00000391835.1	TSL:1	c.762G>T	p.Gln254His	missense	Exon 5 of 5	ENSP00000375711.1	Q96B36-3
	AKT1S1	ENST00000391832.7	TSL:1	c.702G>T	p.Gln234His	missense	Exon 5 of 5	ENSP00000375708.3	Q96B36-1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000304 AC: 5 AN: 164524 AF XY: 0.0000338

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000744

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000222 AC: 31 AN: 1395908 Hom.: 0 Cov.: 30 AF XY: 0.0000218 AC XY: 15 AN XY: 687428

African (AFR) AF: 0.00 AC: 0 AN: 30920

American (AMR) AF: 0.00 AC: 0 AN: 37236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24916

East Asian (EAS) AF: 0.00 AC: 0 AN: 35004

South Asian (SAS) AF: 0.00 AC: 0 AN: 79230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 0.0000288 AC: 31 AN: 1076364

Other (OTH) AF: 0.00 AC: 0 AN: 57654

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152246 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74380

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.00000860 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.090
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.032	D
Polyphen		0.99	D
Vest4		0.12
MutPred		0.20		Loss of disorder (P = 0.1016)
MVP		0.75
MPC		1.6
ClinPred		0.51	D
GERP RS		4.1
Varity_R		0.54
gMVP		0.14
Mutation Taster		=69/31	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

dbSNP: rs373953482; hg19: chr19-50373243;