rs1026192345

Variant names:

• chr2-29920569-A-C
• rs1026192345
• NM_004304.5:c.91T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-29920569-A-C
• chr2-29920569-A-G
• chr2-29920569-A-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_004304.5(ALK):​c.91T>G​(p.Ser31Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000903 in 1,439,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S31T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: ALK NM_004304.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.781
• Publications: 1 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, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000233862 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07762453).
• BS2: High AC in GnomAdExome4 at 13 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.91T>G	p.Ser31Ala	missense	Exon 1 of 29	NP_004295.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALK	ENST00000389048.8	TSL:1 MANE Select	c.91T>G	p.Ser31Ala	missense	Exon 1 of 29	ENSP00000373700.3
	ENSG00000233862	ENST00000669284.1		n.157+34680T>G		intron	N/A
	ENSG00000233862	ENST00000769926.1		n.534+5650T>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000903 AC: 13 AN: 1439882 Hom.: 0 Cov.: 31 AF XY: 0.00000979 AC XY: 7 AN XY: 714744

African (AFR) AF: 0.0000302 AC: 1 AN: 33160

American (AMR) AF: 0.00 AC: 0 AN: 43058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25786

East Asian (EAS) AF: 0.00 AC: 0 AN: 38950

South Asian (SAS) AF: 0.00 AC: 0 AN: 84290

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44652

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5452

European-Non Finnish (NFE) AF: 0.0000109 AC: 12 AN: 1104954

Other (OTH) AF: 0.00 AC: 0 AN: 59580

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.29	T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.78
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.039
Sift	Benign	0.038	D
Sift4G	Benign	0.076	T
Polyphen		0.0070	B
Vest4		0.068
MutPred		0.14		Loss of phosphorylation at S31 (P = 0.0074)
MVP		0.64
MPC		0.14
ClinPred		0.11	T
GERP RS		2.8
Varity_R		0.049
gMVP		0.13
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: rs1026192345; hg19: chr2-30143435;