Variant 2-287768-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001002919.3(ALKAL2):c.68G>C(p.Arg23Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000186 in 1,423,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 0 hom. )

Consequence

ALKAL2
NM_001002919.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.993

Variant links:

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 links:

ENSG00000228643 (HGNC:):

ENSG00000228643 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.021181792).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALKAL2	NM_001002919.3 linkuse as main transcript	c.68G>C	p.Arg23Pro	missense_variant	2/6	ENST00000403610.9	NP_001002919.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ALKAL2	ENST00000403610.9 linkuse as main transcript	c.68G>C	p.Arg23Pro	missense_variant	2/6	1	NM_001002919.3	ENSP00000384604.3	Q6UX46-1
ALKAL2	ENST00000452023.1 linkuse as main transcript	c.68G>C	p.Arg23Pro	missense_variant	2/5	3		ENSP00000389939.1	A0A0B4J1W8
ENSG00000228643	ENST00000427831.1 linkuse as main transcript	n.164+654C>G		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

151970

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000284

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000391

AC:

AN:

53688

Hom.:

AF XY:

0.000284

AC XY:

AN XY:

31648

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00138

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000209

Gnomad NFE exome

AF:

0.000625

Gnomad OTH exome

AF:

0.000644

GnomAD4 exome

AF:

0.000186

AC:

237

AN:

1271186

Hom.:

Cov.:

AF XY:

0.000192

AC XY:

120

AN XY:

625084

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000508

Gnomad4 ASJ exome

AF:

0.00116

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000158

Gnomad4 FIN exome

AF:

0.000336

Gnomad4 NFE exome

AF:

0.000188

Gnomad4 OTH exome

AF:

0.000114

GnomAD4 genome

AF:

0.000184

AC:

AN:

151970

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74226

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000284

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.000200

ExAC

AF:

0.0000737

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2022

The c.68G>C (p.R23P) alteration is located in exon 2 (coding exon 1) of the FAM150B gene. This alteration results from a G to C substitution at nucleotide position 68, causing the arginine (R) at amino acid position 23 to be replaced by a proline (P). 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

Benign

0.068

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Benign

0.028

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.39

T;T

M_CAP

Benign

0.072

MetaRNN

Benign

0.021

T;T

MetaSVM

Benign

-1.0

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.57

N;N

REVEL

Benign

0.037

Sift

Benign

0.10

T;T

Sift4G

Benign

0.21

T;T

Polyphen

0.0040

B;.

Vest4

0.12

MVP

0.030

MPC

0.27

ClinPred

0.051

GERP RS

-4.6

Varity_R

0.078

gMVP

0.43

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over