NM_001267550.2:c.30952G>A

Variant names:

• chr2-178696120-C-T
• rs73038324
• NM_001267550.2:c.30952G>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.30952G>A​(p.Glu10318Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00684 in 1,551,666 control chromosomes in the GnomAD database, including 559 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (321 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (238 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: 1.21
• Publications: 8 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002067268).
• BP6: Variant 2-178696120-C-T is Benign according to our data. Variant chr2-178696120-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.114 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.30952G>A	p.Glu10318Lys	missense	Exon 114 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.30001G>A	p.Glu10001Lys	missense	Exon 112 of 313	NP_001243779.1
	TTN	NM_133378.4		c.27220G>A	p.Glu9074Lys	missense	Exon 111 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.30952G>A	p.Glu10318Lys	missense	Exon 114 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.30952G>A	p.Glu10318Lys	missense	Exon 114 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.30676G>A	p.Glu10226Lys	missense	Exon 112 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0336 AC: 5102 AN: 151930 Hom.: 317 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000574

Gnomad OTH AF: 0.0230

GnomAD2 exomes AF: 0.00775 AC: 1231 AN: 158840 AF XY: 0.00604

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.00561

Gnomad ASJ exome AF: 0.00545

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000807

Gnomad OTH exome AF: 0.00493

GnomAD4 exome AF: 0.00392 AC: 5481 AN: 1399618 Hom.: 238 Cov.: 31 AF XY: 0.00347 AC XY: 2393 AN XY: 690394

African (AFR) AF: 0.124 AC: 3922 AN: 31628

American (AMR) AF: 0.00638 AC: 228 AN: 35716

Ashkenazi Jewish (ASJ) AF: 0.00710 AC: 179 AN: 25220

East Asian (EAS) AF: 0.0000559 AC: 2 AN: 35796

South Asian (SAS) AF: 0.000303 AC: 24 AN: 79292

European-Finnish (FIN) AF: 0.0000203 AC: 1 AN: 49292

Middle Eastern (MID) AF: 0.00667 AC: 38 AN: 5696

European-Non Finnish (NFE) AF: 0.000541 AC: 584 AN: 1078978

Other (OTH) AF: 0.00867 AC: 503 AN: 58000

GnomAD4 genome AF: 0.0337 AC: 5125 AN: 152048 Hom.: 321 Cov.: 32 AF XY: 0.0325 AC XY: 2417 AN XY: 74362

African (AFR) AF: 0.116 AC: 4833 AN: 41490

American (AMR) AF: 0.0116 AC: 178 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

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

European-Non Finnish (NFE) AF: 0.000574 AC: 39 AN: 67902

Other (OTH) AF: 0.0227 AC: 48 AN: 2110

Alfa AF: 0.0125 Hom.: 332

Bravo AF: 0.0387

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0975 AC: 347

ESP6500EA AF: 0.00114 AC: 9

ExAC AF: 0.00649 AC: 606

Asia WGS AF: 0.00779 AC: 28 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	3	not provided (3)
-	-	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	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	0.17
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.97	T
PhyloP100		1.2
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.13
Sift	Uncertain	0.025	D
Polyphen		0.33	B
Vest4		0.26
MVP		0.28
MPC		0.10
ClinPred		0.018	T
GERP RS		5.8
Mutation Taster		=80/20	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: rs73038324; hg19: chr2-179560847;