2-178563747-G-T

Variant names:

• chr2-178563747-G-T
• rs55933739
• NM_001267550.2:c.82385C>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.82385C>A​(p.Thr27462Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00324 in 1,613,638 control chromosomes in the GnomAD database, including 102 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T27462M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.015 (44 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (58 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 5.27
• Publications: 7 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=0.0024363399).
• BP6: Variant 2-178563747-G-T is Benign according to our data. Variant chr2-178563747-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0507 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.82385C>A	p.Thr27462Lys	missense	Exon 326 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.77462C>A	p.Thr25821Lys	missense	Exon 276 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.74681C>A	p.Thr24894Lys	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.82385C>A	p.Thr27462Lys	missense	Exon 326 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.82229C>A	p.Thr27410Lys	missense	Exon 324 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.82109C>A	p.Thr27370Lys	missense	Exon 324 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 2263 AN: 152018 Hom.: 45 Cov.: 33

Gnomad AFR AF: 0.0498

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00564

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.00451 AC: 1121 AN: 248482 AF XY: 0.00373

Gnomad AFR exome AF: 0.0505

Gnomad AMR exome AF: 0.00273

Gnomad ASJ exome AF: 0.0170

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000409

Gnomad OTH exome AF: 0.00448

GnomAD4 exome AF: 0.00203 AC: 2973 AN: 1461502 Hom.: 58 Cov.: 37 AF XY: 0.00186 AC XY: 1350 AN XY: 727044

African (AFR) AF: 0.0528 AC: 1766 AN: 33470

American (AMR) AF: 0.00331 AC: 148 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0171 AC: 446 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86254

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53394

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5764

European-Non Finnish (NFE) AF: 0.000240 AC: 267 AN: 1111754

Other (OTH) AF: 0.00509 AC: 307 AN: 60364

GnomAD4 genome AF: 0.0149 AC: 2262 AN: 152136 Hom.: 44 Cov.: 33 AF XY: 0.0142 AC XY: 1059 AN XY: 74378

African (AFR) AF: 0.0496 AC: 2060 AN: 41508

American (AMR) AF: 0.00563 AC: 86 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 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: 0.000397 AC: 27 AN: 67994

Other (OTH) AF: 0.0166 AC: 35 AN: 2112

Alfa AF: 0.00525 Hom.: 25

Bravo AF: 0.0174

ESP6500AA AF: 0.0468 AC: 179

ESP6500EA AF: 0.00109 AC: 9

ExAC AF: 0.00515 AC: 622

EpiCase AF: 0.000764

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	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;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy (1)
-	-	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	0.090
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	11
DANN	Benign	0.69
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.77
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.14	N
PhyloP100		5.3
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.23
Sift	Uncertain	0.0060	D
Polyphen		0.033	B
Vest4		0.26
MVP		0.16
MPC		0.10
ClinPred		0.030	T
GERP RS		0.93
Mutation Taster		=93/7	polymorphism

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: rs55933739; hg19: chr2-179428474; COSMIC: COSV99045620; COSMIC: COSV99045620;