2-178563334-C-T

Variant names:

• chr2-178563334-C-T
• rs11896637
• NM_001267550.2:c.82798G>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.82798G>A​(p.Ala27600Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00654 in 1,613,570 control chromosomes in the GnomAD database, including 523 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (267 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (256 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: 5.02
• Publications: 9 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=0.0016045868).
• BP6: Variant 2-178563334-C-T is Benign according to our data. Variant chr2-178563334-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 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.82798G>A	p.Ala27600Thr	missense	Exon 326 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.77875G>A	p.Ala25959Thr	missense	Exon 276 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.75094G>A	p.Ala25032Thr	missense	Exon 275 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.82798G>A	p.Ala27600Thr	missense	Exon 326 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.82642G>A	p.Ala27548Thr	missense	Exon 324 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.82522G>A	p.Ala27508Thr	missense	Exon 324 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0323 AC: 4910 AN: 152036 Hom.: 265 Cov.: 33

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000765

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.00856 AC: 2123 AN: 248072 AF XY: 0.00655

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.00554

Gnomad ASJ exome AF: 0.00558

Gnomad EAS exome AF: 0.000280

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000732

Gnomad OTH exome AF: 0.00415

GnomAD4 exome AF: 0.00385 AC: 5620 AN: 1461416 Hom.: 256 Cov.: 37 AF XY: 0.00338 AC XY: 2456 AN XY: 726998

African (AFR) AF: 0.118 AC: 3942 AN: 33460

American (AMR) AF: 0.00597 AC: 267 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00700 AC: 183 AN: 26128

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39624

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53396

Middle Eastern (MID) AF: 0.00625 AC: 36 AN: 5764

European-Non Finnish (NFE) AF: 0.000604 AC: 671 AN: 1111718

Other (OTH) AF: 0.00810 AC: 489 AN: 60360

GnomAD4 genome AF: 0.0324 AC: 4925 AN: 152154 Hom.: 267 Cov.: 33 AF XY: 0.0314 AC XY: 2336 AN XY: 74372

African (AFR) AF: 0.111 AC: 4606 AN: 41510

American (AMR) AF: 0.0127 AC: 194 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5150

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.000765 AC: 52 AN: 67994

Other (OTH) AF: 0.0217 AC: 46 AN: 2116

Alfa AF: 0.0124 Hom.: 226

Bravo AF: 0.0373

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0975 AC: 398

ESP6500EA AF: 0.000951 AC: 8

ExAC AF: 0.0105 AC: 1273

Asia WGS AF: 0.00722 AC: 26 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000830

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	3	not provided (3)
-	-	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	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Benign	0.93
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.078
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		5.0
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.087
Sift	Benign	0.13	T
Polyphen		0.020	B
Vest4		0.17
MPC		0.084
ClinPred		0.031	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=98/2	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: rs11896637; hg19: chr2-179428061;