2-203049890-T-A

Position:

• chr2-203049890-T-A

Variant summary

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

The NM_001378026.1(NBEAL1):​c.220T>A​(p.Cys74Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000498 in 1,404,780 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: NBEAL1 NM_001378026.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.58

Genes affected

NBEAL1 (HGNC:20681): (neurobeachin like 1) Predicted to enable protein kinase binding activity. Predicted to be involved in protein localization. Predicted to be active in cytosol and membrane. [provided by Alliance of Genome Resources, Apr 2022]

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/exons	MANE	Protein	UniProt
NBEAL1	NM_001378026.1	c.220T>A	p.Cys74Ser	missense_variant	4/56	ENST00000683969.1	NP_001364955.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBEAL1	ENST00000683969.1	c.220T>A	p.Cys74Ser	missense_variant	4/56		NM_001378026.1	ENSP00000508055.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000608 AC: 1 AN: 164432 Hom.: 0 AF XY: 0.0000115 AC XY: 1 AN XY: 86746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000156

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000498 AC: 7 AN: 1404780 Hom.: 0 Cov.: 30 AF XY: 0.00000433 AC XY: 3 AN XY: 692906

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: 0.00000648

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2022

The c.220T>A (p.C74S) alteration is located in exon 4 (coding exon 3) of the NBEAL1 gene. This alteration results from a T to A substitution at nucleotide position 220, causing the cysteine (C) at amino acid position 74 to be replaced by a serine (S). 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	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	23
DANN	Benign	0.89
DEOGEN2	Benign	0.043	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.0	M
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.53
Sift	Benign	0.75	T
Sift4G	Benign	0.33	T
Polyphen		1.0	D
Vest4		0.82
MutPred		0.43		Gain of disorder (P = 0.0092);
MVP		0.55
MPC		0.59
ClinPred		0.88	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1159354664; hg19: chr2-203914613;