NM_001267550.2:c.8467G>T

Variant names:

• chr2-178770234-C-A
• rs33917087
• NM_001267550.2:c.8467G>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.8467G>T​(p.Val2823Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,614,122 control chromosomes in the GnomAD database, including 346 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (25 hom., cov: 32)
  • Exomes 𝑓: 0.019 (321 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:28
• Conservation: PhyloP100: 2.17
• Publications: 19 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 -16 ACMG points.

• BP6: Variant 2-178770234-C-A is Benign according to our data. Variant chr2-178770234-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0156 (2369/152264) while in subpopulation NFE AF = 0.0229 (1556/68020). AF 95% confidence interval is 0.0219. There are 25 homozygotes in GnomAd4. There are 1124 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 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.8467G>T	p.Val2823Phe	missense	Exon 36 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.8467G>T	p.Val2823Phe	missense	Exon 36 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.8467G>T	p.Val2823Phe	missense	Exon 36 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.8467G>T	p.Val2823Phe	missense	Exon 36 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.8467G>T	p.Val2823Phe	missense	Exon 36 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.8191G>T	p.Val2731Phe	missense	Exon 34 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2369 AN: 152146 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.00367

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0234

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0229

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.0144 AC: 3608 AN: 251122 AF XY: 0.0146

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.00876

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0245

Gnomad NFE exome AF: 0.0222

Gnomad OTH exome AF: 0.0155

GnomAD4 exome AF: 0.0189 AC: 27599 AN: 1461858 Hom.: 321 Cov.: 33 AF XY: 0.0185 AC XY: 13436 AN XY: 727232

African (AFR) AF: 0.00299 AC: 100 AN: 33480

American (AMR) AF: 0.0105 AC: 468 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 113 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39694

South Asian (SAS) AF: 0.00262 AC: 226 AN: 86258

European-Finnish (FIN) AF: 0.0230 AC: 1228 AN: 53418

Middle Eastern (MID) AF: 0.00676 AC: 39 AN: 5768

European-Non Finnish (NFE) AF: 0.0221 AC: 24523 AN: 1111986

Other (OTH) AF: 0.0149 AC: 899 AN: 60396

GnomAD4 genome AF: 0.0156 AC: 2369 AN: 152264 Hom.: 25 Cov.: 32 AF XY: 0.0151 AC XY: 1124 AN XY: 74442

African (AFR) AF: 0.00366 AC: 152 AN: 41558

American (AMR) AF: 0.0160 AC: 244 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00606 AC: 21 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4826

European-Finnish (FIN) AF: 0.0234 AC: 248 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0229 AC: 1556 AN: 68020

Other (OTH) AF: 0.0151 AC: 32 AN: 2116

Alfa AF: 0.0198 Hom.: 100

Bravo AF: 0.0152

TwinsUK AF: 0.0200 AC: 74

ALSPAC AF: 0.0259 AC: 100

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.0220 AC: 189

ExAC AF: 0.0144 AC: 1751

Asia WGS AF: 0.00144 AC: 5 AN: 3476

EpiCase AF: 0.0208

EpiControl AF: 0.0232

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	12	not specified (12)
-	-	5	not provided (5)
-	-	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	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Benign	0.94
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0060	T
MetaSVM	Uncertain	-0.0059	T
PhyloP100		2.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.42
Sift	Benign	0.080	T
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.22
MPC		0.51
ClinPred		0.036	T
GERP RS		6.1
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: -7

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs33917087; hg19: chr2-179634961; COSMIC: COSV99045581; COSMIC: COSV99045581;