chr2-178634803-T-C

Variant names:

• chr2-178634803-T-C
• rs2288563
• NM_001267550.2:c.42071A>G

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.42071A>G​(p.His14024Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0236 in 1,612,854 control chromosomes in the GnomAD database, including 661 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (69 hom., cov: 32)
  • Exomes 𝑓: 0.024 (592 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 5.87
• Publications: 17 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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016076267).
• BP6: Variant 2-178634803-T-C is Benign according to our data. Variant chr2-178634803-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0898 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.42071A>G	p.His14024Arg	missense	Exon 229 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.37148A>G	p.His12383Arg	missense	Exon 179 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.34367A>G	p.His11456Arg	missense	Exon 178 of 312	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.42071A>G	p.His14024Arg	missense	Exon 229 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.41915A>G	p.His13972Arg	missense	Exon 227 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.41795A>G	p.His13932Arg	missense	Exon 227 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0215 AC: 3272 AN: 152124 Hom.: 70 Cov.: 32

Gnomad AFR AF: 0.00461

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0232

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.0966

Gnomad SAS AF: 0.00807

Gnomad FIN AF: 0.0452

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0231

Gnomad OTH AF: 0.0216

GnomAD2 exomes AF: 0.0290 AC: 7181 AN: 247948 AF XY: 0.0271

Gnomad AFR exome AF: 0.00505

Gnomad AMR exome AF: 0.0335

Gnomad ASJ exome AF: 0.0142

Gnomad EAS exome AF: 0.103

Gnomad FIN exome AF: 0.0475

Gnomad NFE exome AF: 0.0231

Gnomad OTH exome AF: 0.0271

GnomAD4 exome AF: 0.0239 AC: 34837 AN: 1460612 Hom.: 592 Cov.: 32 AF XY: 0.0233 AC XY: 16952 AN XY: 726568

African (AFR) AF: 0.00410 AC: 137 AN: 33384

American (AMR) AF: 0.0317 AC: 1415 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.0143 AC: 374 AN: 26110

East Asian (EAS) AF: 0.0957 AC: 3793 AN: 39638

South Asian (SAS) AF: 0.00695 AC: 598 AN: 86084

European-Finnish (FIN) AF: 0.0490 AC: 2614 AN: 53382

Middle Eastern (MID) AF: 0.0101 AC: 58 AN: 5758

European-Non Finnish (NFE) AF: 0.0220 AC: 24429 AN: 1111354

Other (OTH) AF: 0.0235 AC: 1419 AN: 60318

GnomAD4 genome AF: 0.0215 AC: 3269 AN: 152242 Hom.: 69 Cov.: 32 AF XY: 0.0220 AC XY: 1636 AN XY: 74424

African (AFR) AF: 0.00459 AC: 191 AN: 41570

American (AMR) AF: 0.0232 AC: 354 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3470

East Asian (EAS) AF: 0.0968 AC: 499 AN: 5156

South Asian (SAS) AF: 0.00745 AC: 36 AN: 4830

European-Finnish (FIN) AF: 0.0452 AC: 480 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0231 AC: 1568 AN: 68000

Other (OTH) AF: 0.0213 AC: 45 AN: 2110

Alfa AF: 0.0232 Hom.: 196

Bravo AF: 0.0199

TwinsUK AF: 0.0251 AC: 93

ALSPAC AF: 0.0228 AC: 88

ESP6500AA AF: 0.00547 AC: 20

ESP6500EA AF: 0.0205 AC: 168

ExAC AF: 0.0291 AC: 3512

Asia WGS AF: 0.0360 AC: 126 AN: 3478

EpiCase AF: 0.0199

EpiControl AF: 0.0215

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	not provided (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Benign	0.94
Eigen	Benign	0.036
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.93	L
PhyloP100		5.9
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.13
Sift	Benign	0.53	T
Vest4		0.28
MPC		0.11
ClinPred		0.015	T
GERP RS		5.0
Mutation Taster		=59/41	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2288563; hg19: chr2-179499530; COSMIC: COSV99045732; COSMIC: COSV99045732;