2-29193706-T-C

Variant names:

• chr2-29193706-T-C
• rs1670283
• NM_004304.5:c.4381A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004304.5(ALK):​c.4381A>G​(p.Ile1461Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.998 in 1,611,610 control chromosomes in the GnomAD database, including 803,064 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1461L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.99 (74833 hom., cov: 32)
  • Exomes 𝑓: 1.0 (728231 hom.)
• Consequence: ALK NM_004304.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:17 O:1
• Conservation: PhyloP100: -0.984
• Publications: 64 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]

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. Located in intracellular membrane-bounded organelle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=7.2734883E-7).
• BP6: Variant 2-29193706-T-C is Benign according to our data. Variant chr2-29193706-T-C is described in ClinVar as Benign. ClinVar VariationId is 133472.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

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.4381A>G	p.Ile1461Val	missense	Exon 29 of 29	NP_004295.2
	ALK	NM_001353765.2		c.1177A>G	p.Ile393Val	missense	Exon 10 of 10	NP_001340694.1	A0A0K2YUJ3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	ENST00000389048.8	TSL:1 MANE Select	c.4381A>G	p.Ile1461Val	missense	Exon 29 of 29	ENSP00000373700.3	Q9UM73
	ALK	ENST00000638605.1	TSL:1	n.1258A>G		non_coding_transcript_exon	Exon 11 of 11
	ALK	ENST00000618119.4	TSL:5	c.3250A>G	p.Ile1084Val	missense	Exon 28 of 28	ENSP00000482733.1	A0A087WZL3

Frequencies

GnomAD3 genomes AF: 0.991 AC: 150841 AN: 152166 Hom.: 74774 Cov.: 32

Gnomad AFR AF: 0.969

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.998

Gnomad ASJ AF: 0.996

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.994

GnomAD2 exomes AF: 0.998 AC: 249995 AN: 250608 AF XY: 0.998

Gnomad AFR exome AF: 0.969

Gnomad AMR exome AF: 0.999

Gnomad ASJ exome AF: 0.996

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.999

GnomAD4 exome AF: 0.999 AC: 1457866 AN: 1459326 Hom.: 728231 Cov.: 75 AF XY: 0.999 AC XY: 724917 AN XY: 725568

African (AFR) AF: 0.967 AC: 32271 AN: 33360

American (AMR) AF: 0.999 AC: 44517 AN: 44560

Ashkenazi Jewish (ASJ) AF: 0.996 AC: 25946 AN: 26046

East Asian (EAS) AF: 1.00 AC: 39656 AN: 39656

South Asian (SAS) AF: 1.00 AC: 86192 AN: 86192

European-Finnish (FIN) AF: 1.00 AC: 53366 AN: 53366

Middle Eastern (MID) AF: 0.998 AC: 5752 AN: 5764

European-Non Finnish (NFE) AF: 1.00 AC: 1109984 AN: 1110102

Other (OTH) AF: 0.998 AC: 60182 AN: 60280

GnomAD4 genome AF: 0.991 AC: 150959 AN: 152284 Hom.: 74833 Cov.: 32 AF XY: 0.992 AC XY: 73842 AN XY: 74450

African (AFR) AF: 0.970 AC: 40297 AN: 41562

American (AMR) AF: 0.998 AC: 15277 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.996 AC: 3458 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5162 AN: 5162

South Asian (SAS) AF: 1.00 AC: 4816 AN: 4816

European-Finnish (FIN) AF: 1.00 AC: 10614 AN: 10614

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68028 AN: 68038

Other (OTH) AF: 0.994 AC: 2101 AN: 2114

Alfa AF: 0.996 Hom.: 185042

Bravo AF: 0.990

TwinsUK AF: 1.00 AC: 3707

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.972 AC: 4283

ESP6500EA AF: 1.00 AC: 8597

ExAC AF: 0.997 AC: 121066

Asia WGS AF: 1.00 AC: 3476 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	Neuroblastoma, susceptibility to, 3 (9)
-	-	5	not specified (6)
-	-	2	not provided (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
1	-	-	Squamous cell lung carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.0090
DANN	Benign	0.53
DEOGEN2	Benign	0.010	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0048	N
LIST_S2	Benign	0.086	T
MetaRNN	Benign	7.3e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.1	N
PhyloP100		-0.98
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.37	N
REVEL	Benign	0.021
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.0040
MPC		0.14
ClinPred		0.0021	T
GERP RS		-0.13
Varity_R		0.017
gMVP		0.075
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1670283; hg19: chr2-29416572; COSMIC: COSV101201052; COSMIC: COSV101201052;