17-40701865-A-T

Position:

• chr17-40701865-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_019016.3(KRT24):​c.684T>A​(p.Asp228Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 26)
• Consequence: KRT24 NM_019016.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.504

Genes affected

KRT24 (HGNC:18527): (keratin 24) This gene encodes a member of the type I (acidic) keratin family, which belongs to the superfamily of intermediate filament (IF) proteins. Keratins are heteropolymeric structural proteins which form the intermediate filament. These filaments, along with actin microfilaments and microtubules, compose the cytoskeleton of epithelial cells. The type I keratin genes are clustered in a region of chromosome 17q12-q21. [provided by RefSeq, Jun 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KRT24	NM_019016.3	c.684T>A	p.Asp228Glu	missense_variant	2/8	ENST00000264651.3	NP_061889.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KRT24	ENST00000264651.3	c.684T>A	p.Asp228Glu	missense_variant	2/8	1	NM_019016.3	ENSP00000264651	P1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 23

GnomAD4 genome Cov.: 26

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

Mar 31, 2023

The c.684T>A (p.D228E) alteration is located in exon 2 (coding exon 2) of the KRT24 gene. This alteration results from a T to A substitution at nucleotide position 684, causing the aspartic acid (D) at amino acid position 228 to be replaced by a glutamic acid (E). 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	0.16
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	0.042	D
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	0.93	D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.64
Sift	Benign	0.066	T
Sift4G	Benign	0.10	T
Polyphen		1.0	D
Vest4		0.43
MutPred		0.61		Loss of ubiquitination at K233 (P = 0.1498);
MVP		0.36
MPC		0.32
ClinPred		0.94	D
GERP RS		3.8
Varity_R		0.18
gMVP		0.38

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-38858117;