rs440446

Variant names:

• chr19-44905910-C-G
• rs440446
• NM_000041.4:c.-24+69C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-44905910-C-G
• chr19-44905910-C-T

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -14 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_StrongBP6_Moderate

The NM_001302688.2(APOE):c.42C>G (p.Asn14Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. Note: NM_001302688.2 is not a MANE Select or MANE Plus Clinical transcript for APOE; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant allele was found at a cumulative frequency of 0.641 (AC=829,123) in the gnomAD database across 1,293,628 control chromosomes, including 269,076 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.854. In-silico predictor (REVEL) 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 0.69 (37025 hom., cov: 29)
  • Exomes 𝑓: 0.63 (232051 hom.)
• Consequence: APOE NM_001302688.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:4
• Conservation: PhyloP100: -2.66
• Publications: 115 publications found

Genes affected

APOE (HGNC:613): (apolipoprotein E) The protein encoded by this gene is a major apoprotein of the chylomicron. It binds to a specific liver and peripheral cell receptor, and is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. This gene maps to chromosome 19 in a cluster with the related apolipoprotein C1 and C2 genes. Mutations in this gene result in familial dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron and VLDL remnants. [provided by RefSeq, Jun 2016]

APOE Gene-Disease associations (from GenCC):

• Alzheimer disease 2

  Inheritance: Unknown, AD Classification: DEFINITIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hyperlipoproteinemia type 3

  Inheritance: AD, AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• lipoprotein glomerulopathy

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• sea-blue histiocyte syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BP6Reputable source reports benign		ClinVar 1-star benign — moderate (BP6); ClinVar germline classification: Benign/Likely Benign, 1 star(s).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.8537 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_001302688.2. 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
	APOE	NM_000041.4	MANE Select	c.-24+69C>G		intron	N/A	NP_000032.1	P02649
	APOE	NM_001302688.2		c.42C>G	p.Asn14Lys	missense	Exon 1 of 4	NP_001289617.1
	APOE	NM_001302691.2		c.-39+69C>G		intron	N/A	NP_001289620.1	A0A0S2Z3D5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APOE	ENST00000252486.9	TSL:1 MANE Select	c.-24+69C>G		intron	N/A	ENSP00000252486.3	P02649
	APOE	ENST00000485628.2	TSL:1	n.46+69C>G		intron	N/A
	APOE	ENST00000434152.5	TSL:2	c.42C>G	p.Asn14Lys	missense	Exon 1 of 4	ENSP00000413653.2	H0Y7L5

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: 0.688	AC:104386	Hom:36967	AN:151714	Cov:29
GnomAD2 exomes	AF: 0.604	AC:84191	Hom:	AN:139394	Cov:
GnomAD4 exome	AF: 0.635	AC:724609	Hom:232051	AN:1141796	Cov:41
GnomAD4 genome	AF: 0.688	AC:104514	Hom:37025	AN:151832	Cov:29
TOPMed (Bravo)	AF: 0.684	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.629	AC:26396	Hom:8733	AN:41952	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.656	AC:1537	Hom:497	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.400	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.700	AC:210	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.563	AC:1961	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.370	AC:2676	Hom:	AN:7230	Cov:
Qatari Genome	AF: 0.528	AC:93	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.403	AC:49190	Hom:9990	AN:121988	Cov:
Turkish Variome	AF: 0.592	AC:916	Hom:263	AN:1546	Cov:
UK10K	AF: 0.661	AC:4995	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.423	AC:3790	Hom:830	AN:8960	Cov:

Showing 16 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.647	18388	28400	0.646	18610	28816
SCHEMA(Schizophrenia)	0.477	19758	41390	0.482	42153	87416

Showing 2 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, single submitter

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	1.3
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.77
DANN	Benign	0.51
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.021	N
GPN-Star LLR	N/A	4.3
GPN-Star score	N/A	-0.34
LIST_S2	Benign	0.20	T
MetaRNN	Benign	9.2e-7	T
MetaSVM	Benign	-1.0	T
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	-2.7
PromoterAI	N/A	-0.032	Neutral
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.0
REVEL	Benign	0.013

Showing 20 of 20 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.040	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.

Other links and lift over

dbSNP: rs440446;

hg19: chr19-45409167;

COSMIC: COSV52986063;

COSMIC: COSV52986063;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar