chr2-178589803-C-T

Variant names:

• chr2-178589803-C-T
• rs199895260
• NM_001267550.2:c.61922G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.61922G>A​(p.Arg20641Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,613,528 control chromosomes in the GnomAD database, including 7 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 0.0024 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (6 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:22
• Conservation: PhyloP100: 7.86
• Publications: 12 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009563625).
• BP6: Variant 2-178589803-C-T is Benign according to our data. Variant chr2-178589803-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47177.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00239 (364/152208) while in subpopulation NFE AF = 0.00355 (241/67982). AF 95% confidence interval is 0.00318. There are 1 homozygotes in GnomAd4. There are 179 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• 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.61922G>A	p.Arg20641Gln	missense	Exon 304 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.56999G>A	p.Arg19000Gln	missense	Exon 254 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.54218G>A	p.Arg18073Gln	missense	Exon 253 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.61922G>A	p.Arg20641Gln	missense	Exon 304 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.61766G>A	p.Arg20589Gln	missense	Exon 302 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.61646G>A	p.Arg20549Gln	missense	Exon 302 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00239 AC: 364 AN: 152090 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00354

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00279 AC: 695 AN: 248926 AF XY: 0.00258

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.000986

Gnomad ASJ exome AF: 0.00527

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00487

Gnomad NFE exome AF: 0.00419

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.00281 AC: 4101 AN: 1461320 Hom.: 6 Cov.: 37 AF XY: 0.00281 AC XY: 2042 AN XY: 726942

African (AFR) AF: 0.000419 AC: 14 AN: 33444

American (AMR) AF: 0.00110 AC: 49 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00364 AC: 95 AN: 26122

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39660

South Asian (SAS) AF: 0.000441 AC: 38 AN: 86246

European-Finnish (FIN) AF: 0.00427 AC: 228 AN: 53402

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5762

European-Non Finnish (NFE) AF: 0.00314 AC: 3494 AN: 1111616

Other (OTH) AF: 0.00263 AC: 159 AN: 60356

GnomAD4 genome AF: 0.00239 AC: 364 AN: 152208 Hom.: 1 Cov.: 33 AF XY: 0.00241 AC XY: 179 AN XY: 74394

African (AFR) AF: 0.000457 AC: 19 AN: 41568

American (AMR) AF: 0.00275 AC: 42 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00396 AC: 42 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00355 AC: 241 AN: 67982

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00316 Hom.: 2

Bravo AF: 0.00212

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000534 AC: 2

ESP6500EA AF: 0.00428 AC: 35

ExAC AF: 0.00271 AC: 328

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00486

EpiControl AF: 0.00480

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not provided (8)
-	-	7	not specified (7)
-	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;C0878544:Cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)
1	-	-	Tip-toe gait (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Benign	0.96
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0096	T
MetaSVM	Uncertain	-0.035	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.46
MVP		0.45
MPC		0.50
ClinPred		0.053	T
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=89/11	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: rs199895260; hg19: chr2-179454530;