NM_004304.5:c.3035C>T

Variant names:

• chr2-29226954-G-A
• rs35073634
• NM_004304.5:c.3035C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004304.5(ALK):​c.3035C>T​(p.Thr1012Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000457 in 1,614,208 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1012T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (3 hom.)
• Consequence: ALK NM_004304.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 2.34
• Publications: 17 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00823161).
• BP6: Variant 2-29226954-G-A is Benign according to our data. Variant chr2-29226954-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 133465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000368 (56/152322) while in subpopulation EAS AF = 0.00637 (33/5184). AF 95% confidence interval is 0.00466. There are 0 homozygotes in GnomAd4. There are 34 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 56 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004304.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	NM_004304.5	MANE Select	c.3035C>T	p.Thr1012Met	missense	Exon 18 of 29	NP_004295.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	ENST00000389048.8	TSL:1 MANE Select	c.3035C>T	p.Thr1012Met	missense	Exon 18 of 29	ENSP00000373700.3
	ALK	ENST00000618119.4	TSL:5	c.1904C>T	p.Thr635Met	missense	Exon 17 of 28	ENSP00000482733.1
	ALK	ENST00000431873.6	TSL:5	n.200C>T		non_coding_transcript_exon	Exon 2 of 14	ENSP00000414027.3

Frequencies

GnomAD3 genomes AF: 0.000374 AC: 57 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00635

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000700 AC: 176 AN: 251444 AF XY: 0.000699

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00620

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000467 AC: 682 AN: 1461886 Hom.: 3 Cov.: 33 AF XY: 0.000461 AC XY: 335 AN XY: 727244

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000918 AC: 24 AN: 26136

East Asian (EAS) AF: 0.0105 AC: 416 AN: 39700

South Asian (SAS) AF: 0.000707 AC: 61 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000135 AC: 150 AN: 1112010

Other (OTH) AF: 0.000480 AC: 29 AN: 60394

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152322 Hom.: 0 Cov.: 32 AF XY: 0.000456 AC XY: 34 AN XY: 74482

African (AFR) AF: 0.000144 AC: 6 AN: 41578

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00637 AC: 33 AN: 5184

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000640 Hom.: 4

Bravo AF: 0.000389

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000684 AC: 83

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Neuroblastoma, susceptibility to, 3 (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.0038
Eigen_PC	Benign	0.080
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.52	N
PhyloP100		2.3
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.33
Sift	Benign	0.25	T
Sift4G	Benign	0.24	T
Polyphen		0.79	P
Vest4		0.17
MVP		0.85
MPC		0.34
ClinPred		0.026	T
GERP RS		5.4
Varity_R		0.051
gMVP		0.72
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs35073634; hg19: chr2-29449820; COSMIC: COSV108227339;