rs1553387094

Positions:

• chr2-29193744-G-A
• chr2-29193744-G-C
• chr2-29193744-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The ENST00000389048.8(ALK):​c.4343C>T​(p.Ser1448Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1448P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALK ENST00000389048.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.08

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

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22108862).
• BP6: Variant 2-29193744-G-A is Benign according to our data. Variant chr2-29193744-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 470871.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALK	NM_004304.5	c.4343C>T	p.Ser1448Phe	missense_variant	29/29	ENST00000389048.8	NP_004295.2
ALK	NM_001353765.2	c.1139C>T	p.Ser380Phe	missense_variant	10/10		NP_001340694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALK	ENST00000389048.8	c.4343C>T	p.Ser1448Phe	missense_variant	29/29	1	NM_004304.5	ENSP00000373700	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neuroblastoma, susceptibility to, 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 470871). This variant has not been reported in the literature in individuals affected with ALK-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1448 of the ALK protein (p.Ser1448Phe). -

Ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Jan 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.062	T;T;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.75	T;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.8	.;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.9	.;D;.
REVEL	Benign	0.076
Sift	Benign	0.057	.;T;.
Sift4G	Benign	0.43	.;T;T
Polyphen		0.66	.;P;.
Vest4		0.24, 0.26
MutPred		0.18		.;Loss of phosphorylation at S1448 (P = 0.0091);.;
MVP		0.70
MPC		0.31
ClinPred		0.85	D
GERP RS		4.5
Varity_R		0.090
gMVP		0.24

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553387094; hg19: chr2-29416610; COSMIC: COSV105929815; COSMIC: COSV105929815;