19-49873131-C-T

Variant names:

• chr19-49873131-C-T
• rs201965042
• NM_001098633.4:c.165G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001098633.4(AKT1S1):​c.165G>A​(p.Ala55Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000803 in 1,540,910 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (4 hom.)
• Consequence: AKT1S1 NM_001098633.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -8.20
• 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-49873131-C-T is Benign according to our data. Variant chr19-49873131-C-T is described in ClinVar as Benign. ClinVar VariationId is 713406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-8.2 with no splicing effect.
• BS2: High AC in GnomAd4 at 574 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.165G>A	p.Ala55Ala	synonymous	Exon 2 of 5	NP_001092103.1	Q96B36-1
	AKT1S1	NM_032375.5		c.225G>A	p.Ala75Ala	synonymous	Exon 2 of 5	NP_115751.3	Q96B36-3
	AKT1S1	NM_001098632.2		c.165G>A	p.Ala55Ala	synonymous	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.165G>A	p.Ala55Ala	synonymous	Exon 2 of 5	ENSP00000341698.5	Q96B36-1
	AKT1S1	ENST00000391835.1	TSL:1	c.225G>A	p.Ala75Ala	synonymous	Exon 2 of 5	ENSP00000375711.1	Q96B36-3
	AKT1S1	ENST00000391832.7	TSL:1	c.165G>A	p.Ala55Ala	synonymous	Exon 2 of 5	ENSP00000375708.3	Q96B36-1

Frequencies

GnomAD3 genomes AF: 0.00377 AC: 573 AN: 152158 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00103 AC: 147 AN: 142792 AF XY: 0.000719

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.000803

Gnomad ASJ exome AF: 0.000121

Gnomad EAS exome AF: 0.0000881

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000216

Gnomad OTH exome AF: 0.000466

GnomAD4 exome AF: 0.000477 AC: 663 AN: 1388636 Hom.: 4 Cov.: 34 AF XY: 0.000403 AC XY: 276 AN XY: 685636

African (AFR) AF: 0.0144 AC: 457 AN: 31708

American (AMR) AF: 0.000723 AC: 26 AN: 35980

Ashkenazi Jewish (ASJ) AF: 0.0000398 AC: 1 AN: 25116

East Asian (EAS) AF: 0.0000278 AC: 1 AN: 35930

South Asian (SAS) AF: 0.0000252 AC: 2 AN: 79398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37216

Middle Eastern (MID) AF: 0.00142 AC: 7 AN: 4916

European-Non Finnish (NFE) AF: 0.000114 AC: 123 AN: 1080442

Other (OTH) AF: 0.000794 AC: 46 AN: 57930

GnomAD4 genome AF: 0.00377 AC: 574 AN: 152274 Hom.: 5 Cov.: 32 AF XY: 0.00379 AC XY: 282 AN XY: 74462

African (AFR) AF: 0.0131 AC: 543 AN: 41560

American (AMR) AF: 0.00105 AC: 16 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67984

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00226 Hom.: 0

Bravo AF: 0.00448

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.028
DANN	Benign	0.86
PhyloP100		-8.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs201965042; hg19: chr19-50376388;