rs56071005

Variant names:

• chr2-29220757-G-A
• rs56071005
• NM_004304.5:c.3594C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-29220757-G-A
• chr2-29220757-G-C
• chr2-29220757-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004304.5(ALK):​c.3594C>T​(p.Leu1198Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,614,006 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (10 hom.)
• Consequence: ALK NM_004304.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.99
• Publications: 2 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 2-29220757-G-A is Benign according to our data. Variant chr2-29220757-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 239824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.99 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00159 (242/152310) while in subpopulation NFE AF = 0.00281 (191/68032). AF 95% confidence interval is 0.00248. There are 2 homozygotes in GnomAd4. There are 110 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 242 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.3594C>T	p.Leu1198Leu	synonymous	Exon 23 of 29	NP_004295.2
	ALK	NM_001353765.2		c.390C>T	p.Leu130Leu	synonymous	Exon 4 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.3594C>T	p.Leu1198Leu	synonymous	Exon 23 of 29	ENSP00000373700.3	Q9UM73
	ALK	ENST00000638605.1	TSL:1	n.471C>T		non_coding_transcript_exon	Exon 5 of 11
	ALK	ENST00000618119.4	TSL:5	c.2463C>T	p.Leu821Leu	synonymous	Exon 22 of 28	ENSP00000482733.1	A0A087WZL3

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 242 AN: 152192 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00281

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00137 AC: 344 AN: 251078 AF XY: 0.00141

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000925

Gnomad NFE exome AF: 0.00261

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00253 AC: 3696 AN: 1461696 Hom.: 10 Cov.: 31 AF XY: 0.00246 AC XY: 1787 AN XY: 727150

African (AFR) AF: 0.000269 AC: 9 AN: 33472

American (AMR) AF: 0.0000894 AC: 4 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00148 AC: 79 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00315 AC: 3501 AN: 1111860

Other (OTH) AF: 0.00166 AC: 100 AN: 60386

GnomAD4 genome AF: 0.00159 AC: 242 AN: 152310 Hom.: 2 Cov.: 32 AF XY: 0.00148 AC XY: 110 AN XY: 74474

African (AFR) AF: 0.000722 AC: 30 AN: 41562

American (AMR) AF: 0.000588 AC: 9 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00281 AC: 191 AN: 68032

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00210 Hom.: 2

Bravo AF: 0.00148

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00255

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Neuroblastoma, susceptibility to, 3 (6)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	ALK-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	3.5
DANN	Benign	0.69
PhyloP100		2.0
Mutation Taster		=95/5	polymorphism

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: rs56071005; hg19: chr2-29443623; COSMIC: COSV66586064; COSMIC: COSV66586064;