chr2-286153-G-A

Position:

• chr2-286153-G-A

Variant summary

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

The NM_001002919.3(ALKAL2):​c.358C>T​(p.His120Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,600 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: 0.0000055 (0 hom.)
• Consequence: ALKAL2 NM_001002919.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.56

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]

ALKAL2 (HGNC:):

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
ALKAL2	NM_001002919.3	c.358C>T	p.His120Tyr	missense_variant	4/6	ENST00000403610.9	NP_001002919.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALKAL2	ENST00000403610.9	c.358C>T	p.His120Tyr	missense_variant	4/6	1	NM_001002919.3	ENSP00000384604.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461600 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727070

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: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

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

May 24, 2023

The c.358C>T (p.H120Y) alteration is located in exon 4 (coding exon 3) of the FAM150B gene. This alteration results from a C to T substitution at nucleotide position 358, causing the histidine (H) at amino acid position 120 to be replaced by a tyrosine (Y). 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	0.48
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;.;.;.;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.75	T;T;.;T;T;T
M_CAP	Benign	0.0065	T
MetaRNN	Uncertain	0.73	D;D;D;D;D;D
MetaSVM	Benign	-0.48	T
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.6	D;D;D;.;D;D
REVEL	Uncertain	0.32
Sift	Benign	0.074	T;T;T;.;T;T
Sift4G	Benign	0.088	T;T;T;T;T;T
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.70
MVP		0.14
MPC		0.31
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.30
gMVP		0.46

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: rs377467726; hg19: chr2-286153;