NM_004304.5:c.*246G>A

Variant names:

• chr2-29192978-C-T
• rs1668908633
• NM_004304.5:c.*246G>A

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Strong

The NM_004304.5(ALK):c.*246G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALK NM_004304.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.801
• Publications: 0 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, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), ClinGen
• spastic diplegia

  Inheritance: AD Classification: MODERATE Submitted by: PanelApp Australia

CLIP4 (HGNC:26108): (CAP-Gly domain containing linker protein family member 4) Predicted to enable microtubule plus-end binding activity. Predicted to be involved in cytoplasmic microtubule organization. Predicted to be active in cell cortex; microtubule plus-end; and nucleus. [provided by Alliance of Genome Resources, Jun 2026]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ALK NM_004304.5	MANE Select	c.*246G>A	3_prime_UTR	Exon 29 of 29	Prot: NP_004295.2
	ALK NM_001353765.2		c.*246G>A	3_prime_UTR	Exon 10 of 10	Prot: NP_001340694.1 UniProt:

ALK NM_004304.5

MANE Select

HGVSc / HGVSpc.*246G>A

Exon rankExon 29 of 29

3_prime_UTR

Prot: NP_004295.2

ALK NM_001353765.2

HGVSc / HGVSpc.*246G>A

Exon rankExon 10 of 10

3_prime_UTR

Prot: NP_001340694.1UniProt: A0A0K2YUJ3A0A286YF68

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ALK ENST00000389048.8	TSL:1MANE Select	c.*246G>A	3_prime_UTR	Exon 29 of 29	Prot: ENSP00000373700.3 UniProt:
	ALK ENST00000618119.4	TSL:5	c.*246G>A	3_prime_UTR	Exon 28 of 28	Prot: ENSP00000482733.1 UniProt:
	ALK ENST00000642122.1		c.*246G>A	3_prime_UTR	Exon 10 of 10	Prot: ENSP00000493203.1 UniProt:

ALK ENST00000389048.8

TSL:1MANE Select

HGVSc / HGVSpc.*246G>A

Exon rankExon 29 of 29

3_prime_UTR

Prot: ENSP00000373700.3UniProt: Q9UM73

ALK ENST00000618119.4

TSL:5

HGVSc / HGVSpc.*246G>A

Exon rankExon 28 of 28

3_prime_UTR

Prot: ENSP00000482733.1UniProt: A0A087WZL3

ALK ENST00000642122.1

HGVSc / HGVSpc.*246G>A

Exon rankExon 10 of 10

3_prime_UTR

Prot: ENSP00000493203.1UniProt: A0A286YF68

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:3
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neuroblastoma, susceptibility to, 3 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	15
BayesDel_noAF	Benign	-0.82
CADD	Benign	13
DANN	Benign	0.49
GPN-Star LLR	N/A	-2.4
GPN-Star score	N/A	2.4
PhyloP100	Benign	0.80

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1668908633;

hg19: chr2-29415844;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar