2-178724086-C-T

Variant names:

• chr2-178724086-C-T
• rs72648964
• NM_001267550.2:c.21173G>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.21173G>A​(p.Gly7058Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,613,314 control chromosomes in the GnomAD database, including 10 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. G7058R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (7 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:18
• Conservation: PhyloP100: 2.76
• 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]

ENSG00000267784 (HGNC:):

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=0.008618474).
• BP6: Variant 2-178724086-C-T is Benign according to our data. Variant chr2-178724086-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46682.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00333 (507/152230) while in subpopulation AFR AF = 0.00895 (372/41554). AF 95% confidence interval is 0.0082. There are 3 homozygotes in GnomAd4. There are 253 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.21173G>A	p.Gly7058Asp	missense	Exon 73 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.20222G>A	p.Gly6741Asp	missense	Exon 71 of 313	NP_001243779.1
	TTN	NM_133378.4		c.17441G>A	p.Gly5814Asp	missense	Exon 70 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.21173G>A	p.Gly7058Asp	missense	Exon 73 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.21173G>A	p.Gly7058Asp	missense	Exon 73 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.20897G>A	p.Gly6966Asp	missense	Exon 71 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00333 AC: 506 AN: 152112 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00180 AC: 444 AN: 247242 AF XY: 0.00161

Gnomad AFR exome AF: 0.00939

Gnomad AMR exome AF: 0.00131

Gnomad ASJ exome AF: 0.0169

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000520

Gnomad OTH exome AF: 0.00250

GnomAD4 exome AF: 0.00101 AC: 1476 AN: 1461084 Hom.: 7 Cov.: 33 AF XY: 0.00105 AC XY: 762 AN XY: 726802

African (AFR) AF: 0.00927 AC: 310 AN: 33440

American (AMR) AF: 0.00137 AC: 61 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.0169 AC: 442 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.000499 AC: 43 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00694 AC: 40 AN: 5760

European-Non Finnish (NFE) AF: 0.000389 AC: 432 AN: 1111550

Other (OTH) AF: 0.00245 AC: 148 AN: 60332

GnomAD4 genome AF: 0.00333 AC: 507 AN: 152230 Hom.: 3 Cov.: 33 AF XY: 0.00340 AC XY: 253 AN XY: 74410

African (AFR) AF: 0.00895 AC: 372 AN: 41554

American (AMR) AF: 0.00294 AC: 45 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68000

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00181 Hom.: 7

Bravo AF: 0.00395

ESP6500AA AF: 0.00631 AC: 24

ESP6500EA AF: 0.00109 AC: 9

ExAC AF: 0.00169 AC: 204

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.000819

EpiControl AF: 0.00107

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	3	not provided (3)
-	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	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Benign	0.89
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0086	T
MetaSVM	Uncertain	0.19	D
PhyloP100		2.8
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.63
Sift	Benign	0.33	T
Polyphen		0.47	P
Vest4		0.54
MVP		0.63
MPC		0.26
ClinPred		0.037	T
GERP RS		5.9
Mutation Taster		=79/21	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: rs72648964; hg19: chr2-179588813;