Genetic Variant ALKAL2:c.*442G>A (chr2-279705-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001002919.3(ALKAL2):c.*442G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.302 in 163,834 control chromosomes in the GnomAD database, including 8,263 homozygotes. 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: 𝑓 0.30 ( 7499 hom., cov: 33)

Exomes 𝑓: 0.34 ( 764 hom. )

Consequence

ALKAL2
NM_001002919.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.575

Publications

20 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
ALKAL2	NM_001002919.3 link	c.*442G>A	3_prime_UTR_variant	Exon 6 of 6	ENST00000403610.9	NP_001002919.2
ALKAL2	XM_047443980.1 link	c.*442G>A	3_prime_UTR_variant	Exon 6 of 6		XP_047299936.1
ALKAL2	XM_047443981.1 link	c.*442G>A	3_prime_UTR_variant	Exon 5 of 5		XP_047299937.1
ALKAL2	XM_047443982.1 link	c.*442G>A	3_prime_UTR_variant	Exon 5 of 5		XP_047299938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALKAL2	ENST00000403610.9 link	c.*442G>A		3_prime_UTR_variant	Exon 6 of 6	1	NM_001002919.3	ENSP00000384604.3

Frequencies

GnomAD3 genomes

AF:

0.300

AC:

45552

AN:

151952

Hom.:

7505

Cov.:

show subpopulations

Gnomad AFR

AF:

0.180

Gnomad AMI

AF:

0.238

Gnomad AMR

AF:

0.268

Gnomad ASJ

AF:

0.320

Gnomad EAS

AF:

0.591

Gnomad SAS

AF:

0.271

Gnomad FIN

AF:

0.398

Gnomad MID

AF:

0.351

Gnomad NFE

AF:

0.344

Gnomad OTH

AF:

0.300

GnomAD4 exome

AF:

0.339

AC:

3990

AN:

11766

Hom.:

764

Cov.:

AF XY:

0.334

AC XY:

2059

AN XY:

6158

show subpopulations

African (AFR)

AF:

0.171

AC:

AN:

410

American (AMR)

AF:

0.243

AC:

349

AN:

1436

Ashkenazi Jewish (ASJ)

AF:

0.335

AC:

130

AN:

388

East Asian (EAS)

AF:

0.633

AC:

538

AN:

850

South Asian (SAS)

AF:

0.263

AC:

209

AN:

796

European-Finnish (FIN)

AF:

0.348

AC:

231

AN:

664

Middle Eastern (MID)

AF:

0.182

AC:

AN:

European-Non Finnish (NFE)

AF:

0.340

AC:

2277

AN:

6688

Other (OTH)

AF:

0.355

AC:

182

AN:

512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

122

244

366

488

610

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.300

AC:

45548

AN:

152068

Hom.:

7499

Cov.:

AF XY:

0.303

AC XY:

22482

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.180

AC:

7471

AN:

41508

American (AMR)

AF:

0.268

AC:

4099

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.320

AC:

1110

AN:

3468

East Asian (EAS)

AF:

0.592

AC:

3064

AN:

5180

South Asian (SAS)

AF:

0.269

AC:

1298

AN:

4824

European-Finnish (FIN)

AF:

0.398

AC:

4188

AN:

10524

Middle Eastern (MID)

AF:

0.350

AC:

103

AN:

294

European-Non Finnish (NFE)

AF:

0.344

AC:

23363

AN:

67964

Other (OTH)

AF:

0.301

AC:

635

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1635

3270

4905

6540

8175

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

470

940

1410

1880

2350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.318

Hom.:

18243

Bravo

AF:

0.286

Asia WGS

AF:

0.367

AC:

1270

AN:

3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

3.1

(source)

DANN

Benign

0.57

PhyloP100

0.57

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over