2-178562616-C-T

Variant names:

• chr2-178562616-C-T
• rs376820301
• NM_001267550.2:c.83516G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001267550.2(TTN):​c.83516G>A​(p.Arg27839Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000606 in 1,610,136 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (6 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:10
• Conservation: PhyloP100: 6.12
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.037914336).
• BP6: Variant 2-178562616-C-T is Benign according to our data. Variant chr2-178562616-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 196060.
• BS2: High Homozygotes in GnomAdExome4 at 6 AD,AR gene

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.83516G>A	p.Arg27839Gln	missense	Exon 326 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.78593G>A	p.Arg26198Gln	missense	Exon 276 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.75812G>A	p.Arg25271Gln	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.83516G>A	p.Arg27839Gln	missense	Exon 326 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.83360G>A	p.Arg27787Gln	missense	Exon 324 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.83240G>A	p.Arg27747Gln	missense	Exon 324 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000964

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000416 AC: 102 AN: 245148 AF XY: 0.000444

Gnomad AFR exome AF: 0.000195

Gnomad AMR exome AF: 0.000296

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00112

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000555

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.000630 AC: 918 AN: 1457862 Hom.: 6 Cov.: 37 AF XY: 0.000625 AC XY: 453 AN XY: 724896

African (AFR) AF: 0.000241 AC: 8 AN: 33256

American (AMR) AF: 0.000272 AC: 12 AN: 44152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25936

East Asian (EAS) AF: 0.00141 AC: 56 AN: 39626

South Asian (SAS) AF: 0.000317 AC: 27 AN: 85132

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53240

Middle Eastern (MID) AF: 0.000698 AC: 4 AN: 5730

European-Non Finnish (NFE) AF: 0.000668 AC: 742 AN: 1110562

Other (OTH) AF: 0.00113 AC: 68 AN: 60228

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152274 Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74436

African (AFR) AF: 0.000120 AC: 5 AN: 41574

American (AMR) AF: 0.000720 AC: 11 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5174

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68024

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000611 Hom.: 0

Bravo AF: 0.000468

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000366 AC: 3

ExAC AF: 0.000406 AC: 49

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.000764

EpiControl AF: 0.000535

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	not specified (2)
-	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	Cardiomyopathy (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Benign	0.92
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		6.1
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0060	D
Polyphen		0.75	P
Vest4		0.50
MVP		0.29
MPC		0.12
ClinPred		0.088	T
GERP RS		4.9
Mutation Taster		=25/75	disease causing

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: rs376820301; hg19: chr2-179427343;