rs56132472

Variant names:

• chr2-29193749-G-A
• rs56132472
• NM_004304.5:c.4338C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-29193749-G-A
• chr2-29193749-G-T
• chr2-29193749-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004304.5(ALK):​c.4338C>T​(p.Thr1446Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 1,598,386 control chromosomes in the GnomAD database, including 10,721 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1446T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.10 (972 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9749 hom.)
• Consequence: ALK NM_004304.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.22
• Publications: 20 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-29193749-G-A is Benign according to our data. Variant chr2-29193749-G-A is described in ClinVar as Benign. ClinVar VariationId is 259273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.22 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.119 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.4338C>T	p.Thr1446Thr	synonymous	Exon 29 of 29	NP_004295.2
	ALK	NM_001353765.2		c.1134C>T	p.Thr378Thr	synonymous	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.4338C>T	p.Thr1446Thr	synonymous	Exon 29 of 29	ENSP00000373700.3	Q9UM73
	ALK	ENST00000638605.1	TSL:1	n.1215C>T		non_coding_transcript_exon	Exon 11 of 11
	ALK	ENST00000618119.4	TSL:5	c.3207C>T	p.Thr1069Thr	synonymous	Exon 28 of 28	ENSP00000482733.1	A0A087WZL3

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15833 AN: 152102 Hom.: 973 Cov.: 32

Gnomad AFR AF: 0.0871

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.0827

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0308

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.108

GnomAD2 exomes AF: 0.0928 AC: 22254 AN: 239714 AF XY: 0.0933

Gnomad AFR exome AF: 0.0882

Gnomad AMR exome AF: 0.0526

Gnomad ASJ exome AF: 0.119

Gnomad EAS exome AF: 0.000165

Gnomad FIN exome AF: 0.162

Gnomad NFE exome AF: 0.119

Gnomad OTH exome AF: 0.106

GnomAD4 exome AF: 0.110 AC: 158689 AN: 1446166 Hom.: 9749 Cov.: 36 AF XY: 0.108 AC XY: 77576 AN XY: 717514

African (AFR) AF: 0.0862 AC: 2837 AN: 32908

American (AMR) AF: 0.0574 AC: 2488 AN: 43334

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 2885 AN: 25058

East Asian (EAS) AF: 0.0000759 AC: 3 AN: 39512

South Asian (SAS) AF: 0.0404 AC: 3390 AN: 84004

European-Finnish (FIN) AF: 0.159 AC: 8364 AN: 52738

Middle Eastern (MID) AF: 0.102 AC: 580 AN: 5674

European-Non Finnish (NFE) AF: 0.120 AC: 132138 AN: 1103286

Other (OTH) AF: 0.101 AC: 6004 AN: 59652

GnomAD4 genome AF: 0.104 AC: 15833 AN: 152220 Hom.: 972 Cov.: 32 AF XY: 0.104 AC XY: 7754 AN XY: 74416

African (AFR) AF: 0.0869 AC: 3612 AN: 41542

American (AMR) AF: 0.0826 AC: 1264 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 407 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.0309 AC: 149 AN: 4826

European-Finnish (FIN) AF: 0.164 AC: 1739 AN: 10588

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.122 AC: 8273 AN: 68004

Other (OTH) AF: 0.106 AC: 225 AN: 2114

Alfa AF: 0.109 Hom.: 648

Bravo AF: 0.0978

Asia WGS AF: 0.0160 AC: 59 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.75
DANN	Benign	0.68
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs56132472; hg19: chr2-29416615; COSMIC: COSV66564612; COSMIC: COSV66564612;