2-287832-G-A

Position:

• chr2-287832-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001002919.3(ALKAL2):​c.4C>T​(p.Arg2Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000172 in 1,159,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: ALKAL2 NM_001002919.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.912

Genes affected

ALKAL2 (HGNC:27683): (ALK and LTK ligand 2) Enables receptor signaling protein tyrosine kinase activator activity and receptor tyrosine kinase binding activity. Involved in positive regulation of ERK1 and ERK2 cascade; positive regulation of ERK5 cascade; and positive regulation of neuron projection development. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000228643 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3632331).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALKAL2	NM_001002919.3	c.4C>T	p.Arg2Cys	missense_variant	2/6	ENST00000403610.9	NP_001002919.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALKAL2	ENST00000403610.9	c.4C>T	p.Arg2Cys	missense_variant	2/6	1	NM_001002919.3	ENSP00000384604.3
ALKAL2	ENST00000452023.1	c.4C>T	p.Arg2Cys	missense_variant	2/5	3		ENSP00000389939.1
ENSG00000228643	ENST00000427831.1	n.164+718G>A		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000172 AC: 2 AN: 1159472 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 559966

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: 0.00000206

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Nov 12, 2024

The c.4C>T (p.R2C) alteration is located in exon 2 (coding exon 1) of the FAM150B gene. This alteration results from a C to T substitution at nucleotide position 4, causing the arginine (R) at amino acid position 2 to be replaced by a cysteine (C). 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	0.45
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.034	T;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.37	T;T;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.93	T
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.1	N;.;N
REVEL	Benign	0.16
Sift	Benign	0.033	D;.;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.19
MutPred		0.36		Loss of solvent accessibility (P = 3e-04);Loss of solvent accessibility (P = 3e-04);Loss of solvent accessibility (P = 3e-04);
MVP		0.12
MPC		0.25
ClinPred		0.50	T
GERP RS		1.4
Varity_R		0.10
gMVP		0.42

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: rs1367173443; hg19: chr2-287832;