19-49873070-G-T

Variant names:

• chr19-49873070-G-T
• rs746829615
• NM_001098633.4:c.226C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001098633.4(AKT1S1):​c.226C>A​(p.Arg76Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,401,298 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AKT1S1 NM_001098633.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0990
• 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP7: Synonymous conserved (PhyloP=0.099 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT1S1	NM_001098633.4	c.226C>A	p.Arg76Arg	synonymous_variant	Exon 2 of 5	ENST00000344175.10	NP_001092103.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKT1S1	ENST00000344175.10	c.226C>A	p.Arg76Arg	synonymous_variant	Exon 2 of 5	3	NM_001098633.4	ENSP00000341698.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1401298 Hom.: 0 Cov.: 34 AF XY: 0.00000289 AC XY: 2 AN XY: 691940

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31974

American (AMR) AF: 0.00 AC: 0 AN: 36380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25126

East Asian (EAS) AF: 0.0000276 AC: 1 AN: 36282

South Asian (SAS) AF: 0.00 AC: 0 AN: 79662

European-Finnish (FIN) AF: 0.0000219 AC: 1 AN: 45732

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5234

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082754

Other (OTH) AF: 0.00 AC: 0 AN: 58154

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.006664), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.5
DANN	Benign	0.66
PhyloP100		0.099

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: rs746829615; hg19: chr19-50376327;