2-178767871-C-T

Variant names:

• chr2-178767871-C-T
• rs72647894
• NM_001267550.2:c.9359G>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.9359G>A​(p.Arg3120Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00376 in 1,614,072 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3120P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0039 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (19 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:15
• Conservation: PhyloP100: 2.95
• Publications: 18 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=0.006945014).
• BP6: Variant 2-178767871-C-T is Benign according to our data. Variant chr2-178767871-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47636.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0039 (594/152252) while in subpopulation NFE AF = 0.00595 (405/68026). AF 95% confidence interval is 0.00548. There are 2 homozygotes in GnomAd4. There are 317 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.9359G>A	p.Arg3120Gln	missense	Exon 40 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.9359G>A	p.Arg3120Gln	missense	Exon 40 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.9359G>A	p.Arg3120Gln	missense	Exon 40 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.9359G>A	p.Arg3120Gln	missense	Exon 40 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.9359G>A	p.Arg3120Gln	missense	Exon 40 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.9083G>A	p.Arg3028Gln	missense	Exon 38 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00390 AC: 593 AN: 152134 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00595

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.00410 AC: 1030 AN: 251022 AF XY: 0.00433

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.000637

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00966

Gnomad NFE exome AF: 0.00548

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00374 AC: 5472 AN: 1461820 Hom.: 19 Cov.: 30 AF XY: 0.00379 AC XY: 2755 AN XY: 727214

African (AFR) AF: 0.000806 AC: 27 AN: 33480

American (AMR) AF: 0.000738 AC: 33 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000842 AC: 22 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00410 AC: 354 AN: 86258

European-Finnish (FIN) AF: 0.00869 AC: 464 AN: 53416

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.00392 AC: 4363 AN: 1111976

Other (OTH) AF: 0.00320 AC: 193 AN: 60394

GnomAD4 genome AF: 0.00390 AC: 594 AN: 152252 Hom.: 2 Cov.: 32 AF XY: 0.00426 AC XY: 317 AN XY: 74448

African (AFR) AF: 0.000746 AC: 31 AN: 41536

American (AMR) AF: 0.00118 AC: 18 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00394 AC: 19 AN: 4826

European-Finnish (FIN) AF: 0.0107 AC: 114 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00595 AC: 405 AN: 68026

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.00465 Hom.: 6

Bravo AF: 0.00244

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.00439 AC: 533

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00379

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	not specified (7)
-	-	3	not provided (3)
-	-	1	Atrial fibrillation (1)
-	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	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	Benign	0.19
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.71	T
PhyloP100		2.9
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.27
Sift	Benign	0.23	T
Sift4G	Uncertain	0.021	D
Polyphen		0.99	D
Vest4		0.36
MVP		0.25
MPC		0.32
ClinPred		0.033	T
GERP RS		5.9
PromoterAI		-0.086	Neutral
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs72647894; hg19: chr2-179632598; COSMIC: COSV60007475; COSMIC: COSV60007475;