11-117315598-G-T

Variant names:

• chr11-117315598-G-T
• rs1038127361
• NM_012104.6:c.198C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_012104.6(BACE1):​c.198C>A​(p.Asn66Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,437,530 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: BACE1 NM_012104.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.77

Genes affected

BACE1 (HGNC:933): (beta-secretase 1) This gene encodes a member of the peptidase A1 family of aspartic proteases. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature protease. This transmembrane protease catalyzes the first step in the formation of amyloid beta peptide from amyloid precursor protein. Amyloid beta peptides are the main constituent of amyloid beta plaques, which accumulate in the brains of human Alzheimer's disease patients. [provided by RefSeq, Nov 2015]

CEP164 (HGNC:29182): (centrosomal protein 164) This gene encodes a centrosomal protein involved in microtubule organization, DNA damage response, and chromosome segregation. The encoded protein is required for assembly of primary cilia and localizes to mature centrioles. Defects in this gene are a cause of nephronophthisis-related ciliopathies. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BACE1	NM_012104.6	c.198C>A	p.Asn66Lys	missense_variant	Exon 1 of 9	ENST00000313005.11	NP_036236.1
BACE1	NM_138972.4	c.198C>A	p.Asn66Lys	missense_variant	Exon 1 of 9		NP_620428.1
BACE1	NM_138971.4	c.198C>A	p.Asn66Lys	missense_variant	Exon 1 of 9		NP_620427.1
BACE1	NM_138973.4	c.198C>A	p.Asn66Lys	missense_variant	Exon 1 of 9		NP_620429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BACE1	ENST00000313005.11	c.198C>A	p.Asn66Lys	missense_variant	Exon 1 of 9	1	NM_012104.6	ENSP00000318585.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1437530 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 714890

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.08e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.198C>A (p.N66K) alteration is located in exon 1 (coding exon 1) of the BACE1 gene. This alteration results from a C to A substitution at nucleotide position 198, causing the asparagine (N) at amino acid position 66 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;T;.;.;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.50	T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.0	M;.;M;M;M
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.3	D;D;D;D;D
REVEL	Benign	0.25
Sift	Uncertain	0.012	D;D;T;D;D
Sift4G	Benign	0.068	T;D;D;T;D
Polyphen		0.99	D;.;D;D;P
Vest4		0.59
MutPred		0.50		Gain of methylation at N66 (P = 0.0112);Gain of methylation at N66 (P = 0.0112);Gain of methylation at N66 (P = 0.0112);Gain of methylation at N66 (P = 0.0112);Gain of methylation at N66 (P = 0.0112);
MVP		0.57
MPC		1.9
ClinPred		0.98	D
GERP RS		4.1
Varity_R		0.85
gMVP		0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs1038127361; hg19: chr11-117186314;