12-69610034-C-T

Position:

• chr12-69610034-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_201550.4(LRRC10):​c.805G>A​(p.Val269Ile) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LRRC10 NM_201550.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.558

Genes affected

LRRC10 (HGNC:20264): (leucine rich repeat containing 10) Predicted to enable actin binding activity. Predicted to be involved in cardiac muscle cell development. Predicted to be located in myofibril. Predicted to be active in cytoskeleton and sarcomere. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.051771224).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRRC10	NM_201550.4	c.805G>A	p.Val269Ile	missense_variant	1/1	ENST00000361484.5	NP_963844.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRRC10	ENST00000361484.5	c.805G>A	p.Val269Ile	missense_variant	1/1		NM_201550.4	ENSP00000355166	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dilated Cardiomyopathy, Dominant Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 09, 2023

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 269 of the LRRC10 protein (p.Val269Ile). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 2009564). This variant has not been reported in the literature in individuals affected with LRRC10-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	2.9
DANN	Benign	0.59
DEOGEN2	Benign	0.068	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.028
Sift	Benign	0.52	T
Sift4G	Benign	0.49	T
Polyphen		0.0010	B
Vest4		0.089
MutPred		0.28		Gain of catalytic residue at P273 (P = 0);
MVP		0.37
MPC		0.16
ClinPred		0.064	T
GERP RS		2.9
Varity_R		0.049
gMVP		0.26

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-70003814;