2-178532039-C-T

Variant names:

• chr2-178532039-C-T
• rs68080670
• NM_001267550.2:c.104576G>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.104576G>A​(p.Arg34859Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0143 in 1,613,812 control chromosomes in the GnomAD database, including 247 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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. R34859W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (26 hom., cov: 32)
  • Exomes 𝑓: 0.015 (221 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:31
• Conservation: PhyloP100: 4.53
• Publications: 15 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=0.0042263567).
• BP6: Variant 2-178532039-C-T is Benign according to our data. Variant chr2-178532039-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47675.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 = 0.0122 (1855/152174) while in subpopulation NFE AF = 0.0172 (1170/68010). AF 95% confidence interval is 0.0164. There are 26 homozygotes in GnomAd4. There are 962 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 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.104576G>A	p.Arg34859Gln	missense	Exon 358 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.99653G>A	p.Arg33218Gln	missense	Exon 308 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.96872G>A	p.Arg32291Gln	missense	Exon 307 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.104576G>A	p.Arg34859Gln	missense	Exon 358 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.104420G>A	p.Arg34807Gln	missense	Exon 356 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.104300G>A	p.Arg34767Gln	missense	Exon 356 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1855 AN: 152056 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.00271

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00524

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.0425

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.0125 AC: 3120 AN: 248790 AF XY: 0.0123

Gnomad AFR exome AF: 0.00174

Gnomad AMR exome AF: 0.00336

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0424

Gnomad NFE exome AF: 0.0170

Gnomad OTH exome AF: 0.00928

GnomAD4 exome AF: 0.0146 AC: 21271 AN: 1461638 Hom.: 221 Cov.: 40 AF XY: 0.0143 AC XY: 10373 AN XY: 727098

African (AFR) AF: 0.00215 AC: 72 AN: 33478

American (AMR) AF: 0.00371 AC: 166 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00138 AC: 36 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00246 AC: 212 AN: 86254

European-Finnish (FIN) AF: 0.0414 AC: 2209 AN: 53378

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0160 AC: 17820 AN: 1111842

Other (OTH) AF: 0.0125 AC: 752 AN: 60370

GnomAD4 genome AF: 0.0122 AC: 1855 AN: 152174 Hom.: 26 Cov.: 32 AF XY: 0.0129 AC XY: 962 AN XY: 74398

African (AFR) AF: 0.00270 AC: 112 AN: 41510

American (AMR) AF: 0.00523 AC: 80 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00353 AC: 17 AN: 4818

European-Finnish (FIN) AF: 0.0425 AC: 450 AN: 10590

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

European-Non Finnish (NFE) AF: 0.0172 AC: 1170 AN: 68010

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.0148 Hom.: 86

Bravo AF: 0.00877

TwinsUK AF: 0.0151 AC: 56

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.00268 AC: 11

ESP6500EA AF: 0.0145 AC: 122

ExAC AF: 0.0129 AC: 1560

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.0147

EpiControl AF: 0.0126

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	13	not specified (13)
1	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (3)
-	-	3	not provided (3)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy (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	TTN-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	20
DANN	Benign	0.86
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.34	N
PhyloP100		4.5
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.28
MPC		0.25
ClinPred		0.049	T
GERP RS		5.5
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: rs68080670; hg19: chr2-179396766; COSMIC: COSV99045563; COSMIC: COSV99045563;