2-178534849-C-G

Variant names:

• chr2-178534849-C-G
• rs55886356
• NM_001267550.2:c.101766G>C

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.101766G>C​(p.Gln33922His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 1,608,876 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0075 (6 hom., cov: 33)
  • Exomes 𝑓: 0.010 (106 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:19
• Conservation: PhyloP100: 0.705
• 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=0.008082747).
• BP6: Variant 2-178534849-C-G is Benign according to our data. Variant chr2-178534849-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47641.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00754 (1148/152232) while in subpopulation AMR AF = 0.0178 (272/15284). AF 95% confidence interval is 0.0161. There are 6 homozygotes in GnomAd4. There are 556 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.101766G>C	p.Gln33922His	missense	Exon 358 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.96843G>C	p.Gln32281His	missense	Exon 308 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.94062G>C	p.Gln31354His	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.101766G>C	p.Gln33922His	missense	Exon 358 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.101610G>C	p.Gln33870His	missense	Exon 356 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.101490G>C	p.Gln33830His	missense	Exon 356 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00755 AC: 1148 AN: 152114 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0178

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00720 AC: 1762 AN: 244890 AF XY: 0.00716

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000944

Gnomad NFE exome AF: 0.0109

Gnomad OTH exome AF: 0.00982

GnomAD4 exome AF: 0.0103 AC: 14976 AN: 1456644 Hom.: 106 Cov.: 38 AF XY: 0.0100 AC XY: 7284 AN XY: 724862

African (AFR) AF: 0.00161 AC: 54 AN: 33462

American (AMR) AF: 0.0106 AC: 476 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00149 AC: 39 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00214 AC: 185 AN: 86252

European-Finnish (FIN) AF: 0.00134 AC: 65 AN: 48512

Middle Eastern (MID) AF: 0.0118 AC: 68 AN: 5766

European-Non Finnish (NFE) AF: 0.0122 AC: 13535 AN: 1111776

Other (OTH) AF: 0.00918 AC: 554 AN: 60334

GnomAD4 genome AF: 0.00754 AC: 1148 AN: 152232 Hom.: 6 Cov.: 33 AF XY: 0.00747 AC XY: 556 AN XY: 74420

African (AFR) AF: 0.00234 AC: 97 AN: 41534

American (AMR) AF: 0.0178 AC: 272 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4822

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10600

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0109 AC: 741 AN: 68026

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.00957 Hom.: 9

Bravo AF: 0.00793

TwinsUK AF: 0.0116 AC: 43

ALSPAC AF: 0.0140 AC: 54

ESP6500AA AF: 0.00216 AC: 8

ESP6500EA AF: 0.0104 AC: 85

ExAC AF: 0.00677 AC: 818

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0117

EpiControl AF: 0.0146

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	not provided (3)
-	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	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	Ventricular tachycardia;C0878544:Cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	12
DANN	Benign	0.87
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0081	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		0.70
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.41
MutPred		0.83		Loss of stability (P = 0.3253)
MVP		0.35
MPC		0.43
ClinPred		0.087	T
GERP RS		4.0
Mutation Taster		=89/11	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: rs55886356; hg19: chr2-179399576;