chr2-178617362-C-T

Variant names:

• chr2-178617362-C-T
• rs72677237
• NM_001267550.2:c.47723G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.47723G>A​(p.Arg15908His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00641 in 1,582,756 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0054 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (49 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:29
• Conservation: PhyloP100: 7.86
• Publications: 20 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]

ENSG00000271141 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.008752823).
• BP6: Variant 2-178617362-C-T is Benign according to our data. Variant chr2-178617362-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00537 (817/152014) while in subpopulation SAS AF = 0.00808 (39/4828). AF 95% confidence interval is 0.00696. There are 7 homozygotes in GnomAd4. There are 380 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.47723G>A	p.Arg15908His	missense	Exon 254 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.42800G>A	p.Arg14267His	missense	Exon 204 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.40019G>A	p.Arg13340His	missense	Exon 203 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.47723G>A	p.Arg15908His	missense	Exon 254 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.47567G>A	p.Arg15856His	missense	Exon 252 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.47447G>A	p.Arg15816His	missense	Exon 252 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00540 AC: 820 AN: 151896 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00439

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00807

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00753

Gnomad OTH AF: 0.00911

GnomAD2 exomes AF: 0.00680 AC: 1439 AN: 211730 AF XY: 0.00746

Gnomad AFR exome AF: 0.00138

Gnomad AMR exome AF: 0.00469

Gnomad ASJ exome AF: 0.0239

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00197

Gnomad NFE exome AF: 0.00748

Gnomad OTH exome AF: 0.0111

GnomAD4 exome AF: 0.00652 AC: 9323 AN: 1430742 Hom.: 49 Cov.: 32 AF XY: 0.00676 AC XY: 4795 AN XY: 709828

African (AFR) AF: 0.00160 AC: 51 AN: 31916

American (AMR) AF: 0.00508 AC: 190 AN: 37396

Ashkenazi Jewish (ASJ) AF: 0.0263 AC: 661 AN: 25126

East Asian (EAS) AF: 0.00 AC: 0 AN: 38926

South Asian (SAS) AF: 0.0110 AC: 875 AN: 79496

European-Finnish (FIN) AF: 0.00272 AC: 143 AN: 52608

Middle Eastern (MID) AF: 0.0144 AC: 82 AN: 5680

European-Non Finnish (NFE) AF: 0.00620 AC: 6822 AN: 1100428

Other (OTH) AF: 0.00843 AC: 499 AN: 59166

GnomAD4 genome AF: 0.00537 AC: 817 AN: 152014 Hom.: 7 Cov.: 32 AF XY: 0.00511 AC XY: 380 AN XY: 74316

African (AFR) AF: 0.00142 AC: 59 AN: 41514

American (AMR) AF: 0.00439 AC: 67 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0274 AC: 95 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5124

South Asian (SAS) AF: 0.00808 AC: 39 AN: 4828

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10624

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00750 AC: 509 AN: 67876

Other (OTH) AF: 0.00901 AC: 19 AN: 2108

Alfa AF: 0.00731 Hom.: 17

Bravo AF: 0.00525

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00162 AC: 6

ESP6500EA AF: 0.00880 AC: 72

ExAC AF: 0.00643 AC: 774

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	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	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)
-	-	1	Hypertrophic cardiomyopathy;C0042514:Ventricular tachycardia;C0878544:Cardiomyopathy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Benign	0.96
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.9
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.43
MVP		0.43
MPC		0.52
ClinPred		0.024	T
GERP RS		5.9
Mutation Taster		=99/1	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: rs72677237; hg19: chr2-179482089; COSMIC: COSV107413241;