15-41504848-C-T

Variant names:

• chr15-41504848-C-T
• rs141045322
• NM_002344.6:c.2045G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002344.6(LTK):​c.2045G>A​(p.Arg682Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000153 in 1,613,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. R682G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: LTK NM_002344.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.17
• Publications: 3 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.061202645).
• BS2: High AC in GnomAd4 at 35 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002344.6. 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
	LTK	NM_002344.6	MANE Select	c.2045G>A	p.Arg682Gln	missense	Exon 17 of 20	NP_002335.2
	LTK	NM_206961.4		c.1862G>A	p.Arg621Gln	missense	Exon 16 of 19	NP_996844.1	P29376-4
	LTK	NM_001135685.2		c.1655G>A	p.Arg552Gln	missense	Exon 15 of 18	NP_001129157.1	P29376-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTK	ENST00000263800.11	TSL:1 MANE Select	c.2045G>A	p.Arg682Gln	missense	Exon 17 of 20	ENSP00000263800.6	P29376-1
	LTK	ENST00000355166.9	TSL:1	c.1862G>A	p.Arg621Gln	missense	Exon 16 of 19	ENSP00000347293.5	P29376-4
	LTK	ENST00000561619.5	TSL:1	c.1139G>A	p.Arg380Gln	missense	Exon 11 of 14	ENSP00000458111.1	H3BVG6

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152140 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000232 AC: 58 AN: 250320 AF XY: 0.000207

Gnomad AFR exome AF: 0.000555

Gnomad AMR exome AF: 0.000552

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000145 AC: 212 AN: 1460980 Hom.: 0 Cov.: 33 AF XY: 0.000144 AC XY: 105 AN XY: 726728

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.000471 AC: 21 AN: 44590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26050

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39700

South Asian (SAS) AF: 0.000105 AC: 9 AN: 85988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53252

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.000119 AC: 132 AN: 1111816

Other (OTH) AF: 0.000315 AC: 19 AN: 60344

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74450

African (AFR) AF: 0.000530 AC: 22 AN: 41522

American (AMR) AF: 0.000327 AC: 5 AN: 15302

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000206 Hom.: 0

Bravo AF: 0.000363

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.089	N
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.2
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.35
Sift	Benign	0.27	T
Sift4G	Benign	0.44	T
Polyphen		1.0	D
Vest4		0.32
MVP		0.62
MPC		0.14
ClinPred		0.053	T
GERP RS		-4.0
Varity_R		0.066
gMVP		0.22
Mutation Taster		=98/2	polymorphism

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: rs141045322; hg19: chr15-41797046; COSMIC: COSV99540562; COSMIC: COSV99540562;