rs2288569

Variant names:

• chr2-178593864-C-T
• rs2288569
• NM_001267550.2:c.58436G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-178593864-C-T
• chr2-178593864-C-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.58436G>A​(p.Arg19479His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,609,696 control chromosomes in the GnomAD database, including 22,002 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1986 hom., cov: 32)
  • Exomes 𝑓: 0.15 (20016 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 7.85
• Publications: 32 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=0.002719611).
• BP6: Variant 2-178593864-C-T is Benign according to our data. Variant chr2-178593864-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.426 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.58436G>A	p.Arg19479His	missense	Exon 298 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.53513G>A	p.Arg17838His	missense	Exon 248 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.50732G>A	p.Arg16911His	missense	Exon 247 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.58436G>A	p.Arg19479His	missense	Exon 298 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.58280G>A	p.Arg19427His	missense	Exon 296 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.58160G>A	p.Arg19387His	missense	Exon 296 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21559 AN: 151602 Hom.: 1980 Cov.: 32

Gnomad AFR AF: 0.0757

Gnomad AMI AF: 0.473

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.441

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.129

GnomAD2 exomes AF: 0.178 AC: 43407 AN: 243782 AF XY: 0.182

Gnomad AFR exome AF: 0.0706

Gnomad AMR exome AF: 0.150

Gnomad ASJ exome AF: 0.175

Gnomad EAS exome AF: 0.431

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.162

GnomAD4 exome AF: 0.155 AC: 225335 AN: 1457976 Hom.: 20016 Cov.: 35 AF XY: 0.158 AC XY: 114445 AN XY: 725102

African (AFR) AF: 0.0722 AC: 2393 AN: 33158

American (AMR) AF: 0.149 AC: 6544 AN: 43974

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 4545 AN: 26100

East Asian (EAS) AF: 0.429 AC: 16903 AN: 39434

South Asian (SAS) AF: 0.258 AC: 22008 AN: 85234

European-Finnish (FIN) AF: 0.151 AC: 8049 AN: 53270

Middle Eastern (MID) AF: 0.132 AC: 761 AN: 5754

European-Non Finnish (NFE) AF: 0.139 AC: 154276 AN: 1110850

Other (OTH) AF: 0.164 AC: 9856 AN: 60202

GnomAD4 genome AF: 0.142 AC: 21570 AN: 151720 Hom.: 1986 Cov.: 32 AF XY: 0.147 AC XY: 10899 AN XY: 74096

African (AFR) AF: 0.0755 AC: 3127 AN: 41402

American (AMR) AF: 0.129 AC: 1963 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 605 AN: 3462

East Asian (EAS) AF: 0.441 AC: 2251 AN: 5102

South Asian (SAS) AF: 0.262 AC: 1259 AN: 4802

European-Finnish (FIN) AF: 0.163 AC: 1719 AN: 10526

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.146 AC: 9889 AN: 67892

Other (OTH) AF: 0.138 AC: 291 AN: 2108

Alfa AF: 0.151 Hom.: 5072

Bravo AF: 0.138

TwinsUK AF: 0.134 AC: 496

ALSPAC AF: 0.141 AC: 542

ESP6500AA AF: 0.0765 AC: 284

ESP6500EA AF: 0.147 AC: 1208

ExAC AF: 0.175 AC: 21179

Asia WGS AF: 0.339 AC: 1179 AN: 3476

EpiCase AF: 0.138

EpiControl AF: 0.142

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	0.23
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Benign	0.95
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.18
MPC		0.51
ClinPred		0.025	T
GERP RS		6.2
Mutation Taster		=77/23	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: rs2288569; hg19: chr2-179458591; COSMIC: COSV59894829; COSMIC: COSV59894829;