17-40958834-T-C

Position:

• chr17-40958834-T-C

Variant summary

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

The NM_213656.4(KRT39):​c.1243A>G​(p.Lys415Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,906 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: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KRT39 NM_213656.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.683

Genes affected

KRT39 (HGNC:32971): (keratin 39) 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, Jul 2009]

(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=0.034116447).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KRT39	NM_213656.4	c.1243A>G	p.Lys415Glu	missense_variant	7/7	ENST00000355612.7
LOC107985072	XR_001752886.2	n.81-16663T>C		intron_variant, non_coding_transcript_variant
LOC107985072	XR_001752885.2	n.81-16663T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KRT39	ENST00000355612.7	c.1243A>G	p.Lys415Glu	missense_variant	7/7	1	NM_213656.4	P1
KRT39	ENST00000578078.1	c.*732A>G		3_prime_UTR_variant, NMD_transcript_variant	8/8	1
	ENST00000418393.1	n.386-16663T>C		intron_variant, non_coding_transcript_variant		5
KRT39	ENST00000578029.1	n.443A>G		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000408 AC: 1 AN: 245354 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 132628

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000552

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: 6.87e-7 AC: 1 AN: 1455906 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723690

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	7.1
DANN	Benign	0.56
DEOGEN2	Benign	0.00034	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.12	T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.42	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.11	N
REVEL	Benign	0.074
Sift	Benign	0.89	T
Sift4G	Benign	0.89	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.29		Loss of methylation at K415 (P = 0.0016);
MVP		0.18
MPC		0.17
ClinPred		0.025	T
GERP RS		0.39
Varity_R		0.072
gMVP		0.21

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: rs1274476748; hg19: chr17-39115086;