rs2163008

chr2-178663651-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):c.36508G>A(p.Glu12170Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0988 in 1,612,440 control chromosomes in the GnomAD database, including 16,128 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E12170V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.20 (5345 hom., cov: 31)
  • Exomes 𝑓: 0.088 (10783 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.198

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

LOC124906100 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TTN
• BP4: Computational evidence support a benign effect (MetaRNN=2.773106E-4).
• BP6: Variant 2-178663651-C-T is Benign according to our data. Variant chr2-178663651-C-T is described in ClinVar as [Benign]. Clinvar id is 192215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178663651-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTN	NM_001267550.2	c.36508G>A	p.Glu12170Lys	missense_variant	171/363	ENST00000589042.5
LOC124906100	XR_007087318.1	n.2185+19150C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTN	ENST00000589042.5	c.36508G>A	p.Glu12170Lys	missense_variant	171/363	5	NM_001267550.2	P1
TTN-AS1	ENST00000659121.1	n.502+65970C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30145 AN: 150750 Hom.: 5306 Cov.: 31

Gnomad AFR AF: 0.463

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.0715

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.240

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.118

Gnomad NFE AF: 0.0584

Gnomad OTH AF: 0.164

GnomAD3 exomes AF: 0.146 AC: 36104 AN: 247358 Hom.: 4279 AF XY: 0.139 AC XY: 18717 AN XY: 134618

Gnomad AFR exome AF: 0.472

Gnomad AMR exome AF: 0.253

Gnomad ASJ exome AF: 0.0694

Gnomad EAS exome AF: 0.134

Gnomad SAS exome AF: 0.239

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.0595

Gnomad OTH exome AF: 0.115

GnomAD4 exome AF: 0.0883 AC: 129052 AN: 1461572 Hom.: 10783 Cov.: 34 AF XY: 0.0903 AC XY: 65681 AN XY: 727068

Gnomad4 AFR exome AF: 0.480

Gnomad4 AMR exome AF: 0.251

Gnomad4 ASJ exome AF: 0.0701

Gnomad4 EAS exome AF: 0.107

Gnomad4 SAS exome AF: 0.231

Gnomad4 FIN exome AF: 0.122

Gnomad4 NFE exome AF: 0.0558

Gnomad4 OTH exome AF: 0.111

GnomAD4 genome AF: 0.201 AC: 30251 AN: 150868 Hom.: 5345 Cov.: 31 AF XY: 0.205 AC XY: 15121 AN XY: 73786

Gnomad4 AFR AF: 0.464

Gnomad4 AMR AF: 0.228

Gnomad4 ASJ AF: 0.0715

Gnomad4 EAS AF: 0.130

Gnomad4 SAS AF: 0.239

Gnomad4 FIN AF: 0.121

Gnomad4 NFE AF: 0.0584

Gnomad4 OTH AF: 0.166

Alfa AF: 0.116 Hom.: 1108

Bravo AF: 0.216

TwinsUK AF: 0.0561 AC: 208

ALSPAC AF: 0.0553 AC: 213

ESP6500AA AF: 0.473 AC: 829

ESP6500EA AF: 0.0560 AC: 223

ExAC AF: 0.146 AC: 17622

EpiCase AF: 0.0554

EpiControl AF: 0.0585

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 02, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autosomal recessive limb-girdle muscular dystrophy type 2J Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Early-onset myopathy with fatal cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Tibial muscular dystrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Myopathy, myofibrillar, 9, with early respiratory failure Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	2.7
Dann	Benign	0.72
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.0062	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.00028	T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	0.99	P;P;P;P;P;P
Vest4		0.066
ClinPred		0.0036	T
GERP RS		3.8

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

Publications

LitVar

Other links and lift over

dbSNP: rs2163008; hg19: chr2-179528378; COSMIC: COSV59943020;