2-29193832-C-T

Variant names:

• chr2-29193832-C-T
• rs56181542
• NM_004304.5:c.4255G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_004304.5(ALK):​c.4255G>A​(p.Glu1419Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000671 in 1,610,874 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign 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. E1419D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00069 (2 hom.)
• Consequence: ALK NM_004304.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:6 O:1
• Conservation: PhyloP100: 5.45
• Publications: 14 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 -16 ACMG points.

• BP6: Variant 2-29193832-C-T is Benign according to our data. Variant chr2-29193832-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 133479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000486 (74/152338) while in subpopulation NFE AF = 0.000911 (62/68032). AF 95% confidence interval is 0.000729. There are 0 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 74 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.4255G>A	p.Glu1419Lys	missense	Exon 29 of 29	NP_004295.2
	ALK	NM_001353765.2		c.1051G>A	p.Glu351Lys	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.4255G>A	p.Glu1419Lys	missense	Exon 29 of 29	ENSP00000373700.3	Q9UM73
	ALK	ENST00000638605.1	TSL:1	n.1132G>A		non_coding_transcript_exon	Exon 11 of 11
	ALK	ENST00000618119.4	TSL:5	c.3124G>A	p.Glu1042Lys	missense	Exon 28 of 28	ENSP00000482733.1	A0A087WZL3

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

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: 0.000911

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000464 AC: 115 AN: 247760 AF XY: 0.000485

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000411

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000847

Gnomad OTH exome AF: 0.000666

GnomAD4 exome AF: 0.000690 AC: 1007 AN: 1458536 Hom.: 2 Cov.: 36 AF XY: 0.000677 AC XY: 491 AN XY: 725494

African (AFR) AF: 0.000181 AC: 6 AN: 33196

American (AMR) AF: 0.000453 AC: 20 AN: 44158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25866

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 85726

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.000843 AC: 936 AN: 1110662

Other (OTH) AF: 0.000731 AC: 44 AN: 60200

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74482

African (AFR) AF: 0.0000721 AC: 3 AN: 41582

American (AMR) AF: 0.000523 AC: 8 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000911 AC: 62 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000686 Hom.: 0

Bravo AF: 0.000499

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.000412 AC: 50

EpiCase AF: 0.00136

EpiControl AF: 0.00113

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.032	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.4
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.016	D
Sift4G	Benign	0.12	T
Polyphen		0.86	P
Vest4		0.13
MVP		0.70
MPC		0.20
ClinPred		0.065	T
GERP RS		5.4
Varity_R		0.18
gMVP		0.38
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: -33

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

Other links and lift over

dbSNP: rs56181542; hg19: chr2-29416698; COSMIC: COSV66591946; COSMIC: COSV66591946;