14-104772855-T-C

Variant names:

• chr14-104772855-T-C
• rs2494732
• NM_001382430.1:c.1172+23A>G

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-4 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -4 classification points (ACGS-UK Somatic Oncogenicity v2025). B1_Strong

The NM_001382430.1(AKT1):c.1172+23A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The gene AKT1 is a known oncogene (CancerMine: 20 TSG, 294 oncogene, 149 driver citations). The gene AKT1 is a cancer driver gene (CancerMine: 20 TSG, 294 oncogene, 149 driver citations). The variant allele was found at a cumulative frequency of 0.453 (AC=721,176) in the gnomAD database across 1,592,622 control chromosomes, including 167,152 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.702. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (17643 hom., cov: 33)
  • Exomes 𝑓: 0.45 (149509 hom.)
• Consequence: AKT1 NM_001382430.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.61
• Publications: 4 publications found

Genes affected

AKT1 (HGNC:391): (AKT serine/threonine kinase 1) This gene encodes one of the three members of the human AKT serine-threonine protein kinase family which are often referred to as protein kinase B alpha, beta, and gamma. These highly similar AKT proteins all have an N-terminal pleckstrin homology domain, a serine/threonine-specific kinase domain and a C-terminal regulatory domain. These proteins are phosphorylated by phosphoinositide 3-kinase (PI3K). AKT/PI3K forms a key component of many signalling pathways that involve the binding of membrane-bound ligands such as receptor tyrosine kinases, G-protein coupled receptors, and integrin-linked kinase. These AKT proteins therefore regulate a wide variety of cellular functions including cell proliferation, survival, metabolism, and angiogenesis in both normal and malignant cells. AKT proteins are recruited to the cell membrane by phosphatidylinositol 3,4,5-trisphosphate (PIP3) after phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) by PI3K. Subsequent phosphorylation of both threonine residue 308 and serine residue 473 is required for full activation of the AKT1 protein encoded by this gene. Phosphorylation of additional residues also occurs, for example, in response to insulin growth factor-1 and epidermal growth factor. Protein phosphatases act as negative regulators of AKT proteins by dephosphorylating AKT or PIP3. The PI3K/AKT signalling pathway is crucial for tumor cell survival. Survival factors can suppress apoptosis in a transcription-independent manner by activating AKT1 which then phosphorylates and inactivates components of the apoptotic machinery. AKT proteins also participate in the mammalian target of rapamycin (mTOR) signalling pathway which controls the assembly of the eukaryotic translation initiation factor 4F (eIF4E) complex and this pathway, in addition to responding to extracellular signals from growth factors and cytokines, is disregulated in many cancers. Mutations in this gene are associated with multiple types of cancer and excessive tissue growth including Proteus syndrome and Cowden syndrome 6, and breast, colorectal, and ovarian cancers. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2020]

AKT1 Gene-Disease associations (from GenCC):

• Proteus syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden syndrome 6

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	B1High frequency in general population		GnomAD effective popmax AF >1% — B1 stand-alone benign; GnomAD effective popmax AF = 0.702 — exceeds 1% threshold (B1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001382430.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	AKT1 NM_001382430.1	MANE Select	c.1172+23A>G	intron	Intron 12 of 14	Prot: NP_001369359.1 UniProt:
	AKT1 NM_001014431.2		c.1172+23A>G	intron	Intron 11 of 13	Prot: NP_001014431.1 UniProt:
	AKT1 NM_001014432.2		c.1172+23A>G	intron	Intron 12 of 14	Prot: NP_001014432.1 UniProt:

AKT1 NM_001382430.1

MANE Select

HGVSc / HGVSpc.1172+23A>G

Exon rankIntron 12 of 14

intron

Prot: NP_001369359.1UniProt: P31749-1B0LPE5

AKT1 NM_001014431.2

HGVSc / HGVSpc.1172+23A>G

Exon rankIntron 11 of 13

intron

Prot: NP_001014431.1UniProt: B0LPE5P31749-1

AKT1 NM_001014432.2

HGVSc / HGVSpc.1172+23A>G

Exon rankIntron 12 of 14

intron

Prot: NP_001014432.1UniProt: P31749-1B0LPE5

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	AKT1 ENST00000649815.2	MANE Select	c.1172+23A>G	intron	Intron 12 of 14	Prot: ENSP00000497822.1 UniProt:
	AKT1 ENST00000349310.7	TSL:1	c.1172+23A>G	intron	Intron 12 of 14	Prot: ENSP00000270202.4 UniProt:
	AKT1 ENST00000402615.6	TSL:1	c.1172+23A>G	intron	Intron 11 of 13	Prot: ENSP00000385326.2 UniProt:

AKT1 ENST00000649815.2

MANE Select

HGVSc / HGVSpc.1172+23A>G

Exon rankIntron 12 of 14

intron

Prot: ENSP00000497822.1UniProt: P31749-1

AKT1 ENST00000349310.7

TSL:1

HGVSc / HGVSpc.1172+23A>G

Exon rankIntron 12 of 14

intron

Prot: ENSP00000270202.4UniProt: P31749-1

AKT1 ENST00000402615.6

TSL:1

HGVSc / HGVSpc.1172+23A>G

Exon rankIntron 11 of 13

intron

Prot: ENSP00000385326.2UniProt: P31749-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.476	AC:72230	Hom:17628	AN:151832	Cov:33
GnomAD2 exomes	AF: 0.499	AC:114234	Hom:	AN:229088	Cov:
GnomAD4 exome	AF: 0.450	AC:648878	Hom:149509	AN:1440672	Cov:38
GnomAD4 genome	AF: 0.476	AC:72298	Hom:17643	AN:151950	Cov:33
TOPMed (Bravo)	AF: 0.484	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.454	AC:154175	Hom:35473	AN:339666	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.479	AC:1121	Hom:270	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.727	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.440	AC:132	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.453	AC:5891	Hom:	AN:13004	Cov:
GenomeAsia100K	AF: 0.656	AC:2279	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.700	AC:5059	Hom:	AN:7228	Cov:
Qatari Genome	AF: 0.460	AC:81	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.670	AC:82033	Hom:27552	AN:122400	Cov:
Turkish Variome	AF: 0.429	AC:2834	Hom:632	AN:6608	Cov:
UK10K	AF: 0.415	AC:3136	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.736	AC:6595	Hom:2440	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.423 *	553	1308	0.420 *	2751	6548
BipEx(Bipolar disorder (including schizoaffective))	0.434	12336	28420	0.433	12485	28844
SCHEMA(Schizophrenia)	0.390	29852	76468	0.381	51984	136372

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.29
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.40
DANN	Benign	0.55
GPN-Star LLR	N/A	3.5
GPN-Star score	N/A	-0.23
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	-4.6
PromoterAI	N/A	-0.020	Neutral

Showing 9 of 9 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs2494732;

hg19: chr14-105239192;

COSMIC: COSV62573275;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar