2-29228949-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP3BP6_Moderate

The NM_004304.5(ALK):c.2750C>G(p.Thr917Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000142 in 1,125,708 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T917A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000044 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ALK
NM_004304.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.50

Publications

1 publications found

Variant links:

Genes affected

ALK (HGNC:427): (ALK receptor tyrosine kinase) This gene encodes a receptor tyrosine kinase, which belongs to the insulin receptor superfamily. This protein comprises an extracellular domain, an hydrophobic stretch corresponding to a single pass transmembrane region, and an intracellular kinase domain. It plays an important role in the development of the brain and exerts its effects on specific neurons in the nervous system. This gene has been found to be rearranged, mutated, or amplified in a series of tumours including anaplastic large cell lymphomas, neuroblastoma, and non-small cell lung cancer. The chromosomal rearrangements are the most common genetic alterations in this gene, which result in creation of multiple fusion genes in tumourigenesis, including ALK (chromosome 2)/EML4 (chromosome 2), ALK/RANBP2 (chromosome 2), ALK/ATIC (chromosome 2), ALK/TFG (chromosome 3), ALK/NPM1 (chromosome 5), ALK/SQSTM1 (chromosome 5), ALK/KIF5B (chromosome 10), ALK/CLTC (chromosome 17), ALK/TPM4 (chromosome 19), and ALK/MSN (chromosome X).[provided by RefSeq, Jan 2011]

ALK Gene-Disease associations (from GenCC):

neuroblastoma, susceptibility to, 3
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ALK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.776

BP6

Variant 2-29228949-G-C is Benign according to our data. Variant chr2-29228949-G-C is described in CliVar as Likely_benign. Clinvar id is 3524408.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-29228949-G-C is described in CliVar as Likely_benign. Clinvar id is 3524408.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-29228949-G-C is described in CliVar as Likely_benign. Clinvar id is 3524408.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALK	NM_004304.5 link	c.2750C>G	p.Thr917Arg	missense_variant	Exon 16 of 29	ENST00000389048.8	NP_004295.2	Q9UM73B6D4Y2
ALK	XR_001738688.3 link	n.3668+9C>G		intron_variant	Intron 16 of 17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8 link	c.2750C>G	p.Thr917Arg	missense_variant	Exon 16 of 29	1	NM_004304.5	ENSP00000373700.3		Q9UM73
ALK	ENST00000618119.4 link	c.1619C>G	p.Thr540Arg	missense_variant	Exon 15 of 28	5		ENSP00000482733.1		A0A087WZL3

Frequencies

GnomAD3 genomes

AF:

0.0000435

AC:

AN:

45952

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000928

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000455

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000170

AC:

AN:

176352

AF XY:

0.0000204

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000309

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000142

AC:

AN:

1125708

Hom.:

Cov.:

AF XY:

0.0000199

AC XY:

AN XY:

552584

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000795

AC:

AN:

25170

American (AMR)

AF:

0.0000362

AC:

AN:

27632

Ashkenazi Jewish (ASJ)

AF:

0.0000502

AC:

AN:

19926

East Asian (EAS)

AF:

0.0000963

AC:

AN:

31144

South Asian (SAS)

AF:

0.0000634

AC:

AN:

47302

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42952

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4698

European-Non Finnish (NFE)

AF:

0.00000568

AC:

AN:

880658

Other (OTH)

AF:

0.0000216

AC:

AN:

46226

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.259

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000435

AC:

AN:

45952

Hom.:

Cov.:

AF XY:

0.0000437

AC XY:

AN XY:

22900

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000928

AC:

AN:

10774

American (AMR)

AF:

0.00

AC:

AN:

3588

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1120

East Asian (EAS)

AF:

0.00

AC:

AN:

2580

South Asian (SAS)

AF:

0.00

AC:

AN:

2268

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2654

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0000455

AC:

AN:

21968

Other (OTH)

AF:

0.00

AC:

AN:

590

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:1

Aug 21, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.053

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Benign

-0.64

MutationAssessor

Uncertain

2.7

M;.

PhyloP100

7.5

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.7

D;.

REVEL

Uncertain

0.32

Sift

Uncertain

0.016

D;.

Sift4G

Uncertain

0.013

D;D

Polyphen

0.97

D;.

Vest4

0.86

MutPred

0.26

Loss of ubiquitination at K912 (P = 0.0283);.;

MVP

0.73

MPC

0.75

ClinPred

0.92

GERP RS

5.4

Varity_R

0.57

gMVP

0.91

Mutation Taster

=8/92

disease causing

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over