2-178551932-C-T

Variant names:

• chr2-178551932-C-T
• rs11887722
• NM_001267550.2:c.90968G>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.90968G>A​(p.Arg30323Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00651 in 1,613,532 control chromosomes in the GnomAD database, including 517 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/19 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. R30323T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.033 (264 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (253 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: 2.14
• 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]

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=0.0015034676).
• BP6: Variant 2-178551932-C-T is Benign according to our data. Variant chr2-178551932-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.109 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.90968G>A	p.Arg30323Lys	missense	Exon 335 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.86045G>A	p.Arg28682Lys	missense	Exon 285 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.83264G>A	p.Arg27755Lys	missense	Exon 284 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.90968G>A	p.Arg30323Lys	missense	Exon 335 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.90812G>A	p.Arg30271Lys	missense	Exon 333 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.90692G>A	p.Arg30231Lys	missense	Exon 333 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0324 AC: 4936 AN: 152112 Hom.: 262 Cov.: 33

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.0215

GnomAD2 exomes AF: 0.00854 AC: 2124 AN: 248734 AF XY: 0.00654

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.00545

Gnomad ASJ exome AF: 0.00557

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000693

Gnomad OTH exome AF: 0.00415

GnomAD4 exome AF: 0.00380 AC: 5552 AN: 1461302 Hom.: 253 Cov.: 33 AF XY: 0.00332 AC XY: 2413 AN XY: 726872

African (AFR) AF: 0.118 AC: 3964 AN: 33468

American (AMR) AF: 0.00593 AC: 265 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00697 AC: 182 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86234

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53396

Middle Eastern (MID) AF: 0.00625 AC: 36 AN: 5758

European-Non Finnish (NFE) AF: 0.000531 AC: 590 AN: 1111564

Other (OTH) AF: 0.00815 AC: 492 AN: 60358

GnomAD4 genome AF: 0.0325 AC: 4951 AN: 152230 Hom.: 264 Cov.: 33 AF XY: 0.0316 AC XY: 2354 AN XY: 74416

African (AFR) AF: 0.112 AC: 4645 AN: 41534

American (AMR) AF: 0.0127 AC: 194 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 68020

Other (OTH) AF: 0.0213 AC: 45 AN: 2114

Alfa AF: 0.0122 Hom.: 196

Bravo AF: 0.0375

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0985 AC: 418

ESP6500EA AF: 0.000945 AC: 8

ExAC AF: 0.0106 AC: 1285

Asia WGS AF: 0.00751 AC: 27 AN: 3476

EpiCase AF: 0.000818

EpiControl AF: 0.000830

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	12	not specified (12)
-	-	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	not provided (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	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	0.13
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Benign	0.83
Eigen	Benign	-0.15
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.66	N
PhyloP100		2.1
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.056
Sift	Benign	0.23	T
Polyphen		0.0010	B
Vest4		0.13
MPC		0.085
ClinPred		0.043	T
GERP RS		5.8
Mutation Taster		=97/3	polymorphism (auto)

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: rs11887722; hg19: chr2-179416659;