rs2353005

Variant names:

• chr19-49869505-G-A
• rs2353005
• NM_001098633.4:c.*412C>T

Variant summary

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

The NM_001098633.4(AKT1S1):​c.*412C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 158,598 control chromosomes in the GnomAD database, including 1,018 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.10 (947 hom., cov: 33)
  • Exomes 𝑓: 0.12 (71 hom.)
• Consequence: AKT1S1 NM_001098633.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.776
• Publications: 19 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.141 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT1S1	NM_001098633.4	c.*412C>T		3_prime_UTR_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.*412C>T		3_prime_UTR_variant	Exon 5 of 5	3	NM_001098633.4	ENSP00000341698.5

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15487 AN: 152190 Hom.: 949 Cov.: 33

Gnomad AFR AF: 0.0365

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.0926

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.0912

Gnomad FIN AF: 0.0888

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.112

GnomAD4 exome AF: 0.125 AC: 786 AN: 6290 Hom.: 71 Cov.: 0 AF XY: 0.123 AC XY: 405 AN XY: 3284

African (AFR) AF: 0.0504 AC: 12 AN: 238

American (AMR) AF: 0.0556 AC: 7 AN: 126

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 27 AN: 230

East Asian (EAS) AF: 0.124 AC: 30 AN: 242

South Asian (SAS) AF: 0.0896 AC: 55 AN: 614

European-Finnish (FIN) AF: 0.103 AC: 49 AN: 478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 30

European-Non Finnish (NFE) AF: 0.142 AC: 562 AN: 3956

Other (OTH) AF: 0.117 AC: 44 AN: 376

GnomAD4 genome AF: 0.102 AC: 15477 AN: 152308 Hom.: 947 Cov.: 33 AF XY: 0.0991 AC XY: 7382 AN XY: 74476

African (AFR) AF: 0.0364 AC: 1512 AN: 41576

American (AMR) AF: 0.0923 AC: 1413 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 384 AN: 3472

East Asian (EAS) AF: 0.122 AC: 630 AN: 5178

South Asian (SAS) AF: 0.0919 AC: 444 AN: 4830

European-Finnish (FIN) AF: 0.0888 AC: 943 AN: 10618

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.144 AC: 9774 AN: 68014

Other (OTH) AF: 0.111 AC: 235 AN: 2112

Alfa AF: 0.130 Hom.: 2373

Bravo AF: 0.101

Asia WGS AF: 0.0910 AC: 318 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.47
DANN	Benign	0.69
PhyloP100		-0.78
Mutation Taster		=100/0	polymorphism (auto)

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: rs2353005; hg19: chr19-50372762;