chr2-178563730-T-G

Variant names:

• chr2-178563730-T-G
• rs201958805
• NM_001267550.2:c.82402A>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001267550.2(TTN):​c.82402A>C​(p.Lys27468Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000356 in 1,613,564 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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. K27468N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:8
• Conservation: PhyloP100: 6.07
• Publications: 5 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09309885).
• BP6: Variant 2-178563730-T-G is Benign according to our data. Variant chr2-178563730-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47411.

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.82402A>C	p.Lys27468Gln	missense	Exon 326 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.77479A>C	p.Lys25827Gln	missense	Exon 276 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.74698A>C	p.Lys24900Gln	missense	Exon 275 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.82402A>C	p.Lys27468Gln	missense	Exon 326 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.82246A>C	p.Lys27416Gln	missense	Exon 324 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.82126A>C	p.Lys27376Gln	missense	Exon 324 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152048 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000274 AC: 68 AN: 248628 AF XY: 0.000326

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000551

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000367 AC: 536 AN: 1461516 Hom.: 1 Cov.: 37 AF XY: 0.000352 AC XY: 256 AN XY: 727044

African (AFR) AF: 0.0000598 AC: 2 AN: 33470

American (AMR) AF: 0.000112 AC: 5 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000465 AC: 517 AN: 1111758

Other (OTH) AF: 0.000166 AC: 10 AN: 60366

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152048 Hom.: 0 Cov.: 33 AF XY: 0.000189 AC XY: 14 AN XY: 74252

African (AFR) AF: 0.0000725 AC: 3 AN: 41404

American (AMR) AF: 0.0000656 AC: 1 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 68008

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000363 Hom.: 1

Bravo AF: 0.000234

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000483 AC: 4

ExAC AF: 0.000372 AC: 45

EpiCase AF: 0.000273

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	1	2	not specified (3)
-	1	1	Autosomal recessive limb-girdle muscular dystrophy type 2J (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	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Benign	0.84
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.97	L
PhyloP100		6.1
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.19
Sift	Benign	0.099	T
Polyphen		0.31	B
Vest4		0.38
MVP		0.24
MPC		0.14
ClinPred		0.075	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs201958805; hg19: chr2-179428457;