chr19-49872948-G-A

Variant names:

• chr19-49872948-G-A
• rs149454204
• NM_001098633.4:c.348C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001098633.4(AKT1S1):​c.348C>T​(p.Ser116Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,594,832 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (12 hom.)
• Consequence: AKT1S1 NM_001098633.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.34
• 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 19-49872948-G-A is Benign according to our data. Variant chr19-49872948-G-A is described in ClinVar as [Benign]. Clinvar id is 716506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.35 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0056 (849/151736) while in subpopulation AFR AF = 0.0188 (781/41454). AF 95% confidence interval is 0.0177. There are 8 homozygotes in GnomAd4. There are 414 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 849 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKT1S1	NM_001098633.4	c.348C>T	p.Ser116Ser	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.348C>T	p.Ser116Ser	synonymous_variant	Exon 2 of 5	3	NM_001098633.4	ENSP00000341698.5

Frequencies

GnomAD3 genomes AF: 0.00557 AC: 845 AN: 151614 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00134

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00174 AC: 406 AN: 233162 AF XY: 0.00139

Gnomad AFR exome AF: 0.0202

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00206

Gnomad NFE exome AF: 0.000263

Gnomad OTH exome AF: 0.000690

GnomAD4 exome AF: 0.000816 AC: 1177 AN: 1443096 Hom.: 12 Cov.: 34 AF XY: 0.000713 AC XY: 512 AN XY: 717614

African (AFR) AF: 0.0208 AC: 689 AN: 33096

American (AMR) AF: 0.00148 AC: 65 AN: 44014

Ashkenazi Jewish (ASJ) AF: 0.0000390 AC: 1 AN: 25618

East Asian (EAS) AF: 0.00 AC: 0 AN: 38866

South Asian (SAS) AF: 0.0000472 AC: 4 AN: 84704

European-Finnish (FIN) AF: 0.00124 AC: 57 AN: 46066

Middle Eastern (MID) AF: 0.00176 AC: 10 AN: 5696

European-Non Finnish (NFE) AF: 0.000244 AC: 270 AN: 1105450

Other (OTH) AF: 0.00136 AC: 81 AN: 59586

GnomAD4 genome AF: 0.00560 AC: 849 AN: 151736 Hom.: 8 Cov.: 32 AF XY: 0.00558 AC XY: 414 AN XY: 74178

African (AFR) AF: 0.0188 AC: 781 AN: 41454

American (AMR) AF: 0.00183 AC: 28 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4760

European-Finnish (FIN) AF: 0.00134 AC: 14 AN: 10454

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67890

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00675 Hom.: 2

Bravo AF: 0.00611

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 10, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.41
DANN	Benign	0.73
PhyloP100		-1.3
Mutation Taster		=100/0	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: rs149454204; hg19: chr19-50376205; COSMIC: COSV99680632; COSMIC: COSV99680632;