15-41504849-G-C

Variant names:

• chr15-41504849-G-C
• rs748131904
• NM_002344.6:c.2044C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002344.6(LTK):​c.2044C>G​(p.Arg682Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,766 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LTK NM_002344.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.973

Genes affected

LTK (HGNC:6721): (leukocyte receptor tyrosine kinase) The protein encoded by this gene is a member of the ros/insulin receptor family of tyrosine kinases. Tyrosine-specific phosphorylation of proteins is a key to the control of diverse pathways leading to cell growth and differentiation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LTK	NM_002344.6	c.2044C>G	p.Arg682Gly	missense_variant	Exon 17 of 20	ENST00000263800.11	NP_002335.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTK	ENST00000263800.11	c.2044C>G	p.Arg682Gly	missense_variant	Exon 17 of 20	1	NM_002344.6	ENSP00000263800.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460766 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726620

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2044C>G (p.R682G) alteration is located in exon 17 (coding exon 17) of the LTK gene. This alteration results from a C to G substitution at nucleotide position 2044, causing the arginine (R) at amino acid position 682 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.47	.;T;D;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.55	D;D;D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.0	.;L;.;.
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-3.7	D;D;D;D
REVEL	Uncertain	0.50
Sift	Benign	0.084	T;T;T;T
Sift4G	Benign	0.28	T;T;T;T
Polyphen		0.97	D;P;.;.
Vest4		0.52
MutPred		0.58		.;Loss of MoRF binding (P = 0.0073);.;.;
MVP		0.77
MPC		0.38
ClinPred		0.89	D
GERP RS		2.7
Varity_R		0.17
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs748131904; hg19: chr15-41797047;