2-178534950-C-T

Variant names:

• chr2-178534950-C-T
• rs34924609
• NM_001267550.2:c.101665G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.101665G>A​(p.Val33889Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00539 in 1,612,706 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V33889L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0056 (26 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:23
• Conservation: PhyloP100: 2.63
• Publications: 14 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072075427).
• BP6: Variant 2-178534950-C-T is Benign according to our data. Variant chr2-178534950-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47639.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00352 (536/152310) while in subpopulation NFE AF = 0.00675 (459/68022). AF 95% confidence interval is 0.00624. There are 3 homozygotes in GnomAd4. There are 254 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.101665G>A	p.Val33889Ile	missense	Exon 358 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.96742G>A	p.Val32248Ile	missense	Exon 308 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.93961G>A	p.Val31321Ile	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.101665G>A	p.Val33889Ile	missense	Exon 358 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.101509G>A	p.Val33837Ile	missense	Exon 356 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.101389G>A	p.Val33797Ile	missense	Exon 356 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00352 AC: 536 AN: 152192 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.000849

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00675

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00310 AC: 768 AN: 247810 AF XY: 0.00333

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.000697

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000959

Gnomad NFE exome AF: 0.00604

Gnomad OTH exome AF: 0.00233

GnomAD4 exome AF: 0.00559 AC: 8158 AN: 1460396 Hom.: 26 Cov.: 38 AF XY: 0.00551 AC XY: 4003 AN XY: 726504

African (AFR) AF: 0.00123 AC: 41 AN: 33448

American (AMR) AF: 0.000716 AC: 32 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86250

European-Finnish (FIN) AF: 0.00187 AC: 98 AN: 52414

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00694 AC: 7718 AN: 1111684

Other (OTH) AF: 0.00396 AC: 239 AN: 60340

GnomAD4 genome AF: 0.00352 AC: 536 AN: 152310 Hom.: 3 Cov.: 33 AF XY: 0.00341 AC XY: 254 AN XY: 74470

African (AFR) AF: 0.00113 AC: 47 AN: 41582

American (AMR) AF: 0.000850 AC: 13 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.000849 AC: 9 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00675 AC: 459 AN: 68022

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00544 Hom.: 11

Bravo AF: 0.00346

TwinsUK AF: 0.0105 AC: 39

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00162 AC: 6

ESP6500EA AF: 0.00648 AC: 53

ExAC AF: 0.00330 AC: 399

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	5	not provided (5)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	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	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Hypertrophic cardiomyopathy;C0039240:Supraventricular tachycardia (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)
1	-	-	Tip-toe gait (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Benign	0.81
Eigen	Benign	-0.062
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.45	N
PhyloP100		2.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.060
Sift	Pathogenic	0.0	D
Polyphen		0.0090	B
Vest4		0.10
MVP		0.41
MPC		0.070
ClinPred		0.064	T
GERP RS		5.0
Mutation Taster		=98/2	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: rs34924609; hg19: chr2-179399677;