2-178663651-C-T

Variant names:

• chr2-178663651-C-T
• rs2163008
• NM_001267550.2:c.36508G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. 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. 11/14 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:12
• Conservation: PhyloP100: 0.198
• Publications: 12 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• 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 VariationId is 192215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. 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
	TTN	NM_001267550.2	MANE Select	c.36508G>A	p.Glu12170Lys	missense	Exon 171 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.34265-596G>A		intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.31484-596G>A		intron	N/A	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.36508G>A	p.Glu12170Lys	missense	Exon 171 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.36508G>A	p.Glu12170Lys	missense	Exon 171 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.36232G>A	p.Glu12078Lys	missense	Exon 169 of 361	ENSP00000405517.2

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

GnomAD2 exomes AF: 0.146 AC: 36104 AN: 247358 AF XY: 0.139

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 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

African (AFR) AF: 0.480 AC: 16067 AN: 33470

American (AMR) AF: 0.251 AC: 11217 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0701 AC: 1831 AN: 26128

East Asian (EAS) AF: 0.107 AC: 4254 AN: 39692

South Asian (SAS) AF: 0.231 AC: 19888 AN: 86254

European-Finnish (FIN) AF: 0.122 AC: 6516 AN: 53402

Middle Eastern (MID) AF: 0.0947 AC: 546 AN: 5764

European-Non Finnish (NFE) AF: 0.0558 AC: 62049 AN: 1111792

Other (OTH) AF: 0.111 AC: 6684 AN: 60358

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

African (AFR) AF: 0.464 AC: 19099 AN: 41172

American (AMR) AF: 0.228 AC: 3452 AN: 15156

Ashkenazi Jewish (ASJ) AF: 0.0715 AC: 247 AN: 3456

East Asian (EAS) AF: 0.130 AC: 654 AN: 5034

South Asian (SAS) AF: 0.239 AC: 1134 AN: 4746

European-Finnish (FIN) AF: 0.121 AC: 1272 AN: 10508

Middle Eastern (MID) AF: 0.113 AC: 32 AN: 282

European-Non Finnish (NFE) AF: 0.0584 AC: 3941 AN: 67518

Other (OTH) AF: 0.166 AC: 348 AN: 2096

Alfa AF: 0.120 Hom.: 1196

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.20
Vest4		0.066
ClinPred		0.0036	T
GERP RS		3.8
Mutation Taster		=94/6	polymorphism (auto)

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