7-117721113-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033427.3(CTTNBP2):c.4465A>G(p.Ile1489Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000898 in 1,447,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: CTTNBP2 NM_033427.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.615

Genes affected

CTTNBP2 (HGNC:15679): (cortactin binding protein 2) This gene encodes a protein with six ankyrin repeats and several proline-rich regions. A similar gene in rat interacts with a central regulator of the actin cytoskeleton. [provided by RefSeq, Jul 2008]

LOC105375469 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.032819837).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTTNBP2	NM_033427.3	c.4465A>G	p.Ile1489Val	missense_variant	20/23	ENST00000160373.8
LOC105375469	XR_927902.3	n.89+5142T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTTNBP2	ENST00000160373.8	c.4465A>G	p.Ile1489Val	missense_variant	20/23	1	NM_033427.3	P1
CTTNBP2	ENST00000446636.5	c.2929A>G	p.Ile977Val	missense_variant	18/21	5
CTTNBP2	ENST00000441556.5	c.*2379A>G		3_prime_UTR_variant, NMD_transcript_variant	20/23	5
CTTNBP2	ENST00000445366.1	c.*182A>G		3_prime_UTR_variant, NMD_transcript_variant	3/6	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 250966 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135646

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000898 AC: 13 AN: 1447078 Hom.: 0 Cov.: 27 AF XY: 0.00000971 AC XY: 7 AN XY: 720884

Gnomad4 AFR exome AF: 0.000121

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000637

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000508 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2022

The c.4465A>G (p.I1489V) alteration is located in exon 20 (coding exon 20) of the CTTNBP2 gene. This alteration results from a A to G substitution at nucleotide position 4465, causing the isoleucine (I) at amino acid position 1489 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	0.0030
Dann	Benign	0.27
DEOGEN2	Benign	0.020	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.96	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.079
Sift	Benign	0.46	T
Sift4G	Benign	0.69	T
Polyphen		0.0	B
Vest4		0.034
MutPred		0.14		Loss of methylation at K1487 (P = 0.102);
MVP		0.23
MPC		0.075
ClinPred		0.034	T
GERP RS		-4.8
Varity_R		0.019
gMVP		0.040

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

Publications

LitVar

Other links and lift over

dbSNP: rs1462245041; hg19: chr7-117361167;